KR20200116487A - Urea-substituted aromatic ring-linked dioxynoquinoline compound and its preparation method and use - Google Patents

Abstract

화학식 (I)The present invention relates to a urea-substituted aromatic ring-linked dioxazoline compound of formula (I), or a pharmaceutically acceptable salt, or hydrate thereof. The present disclosure also provides a method of preparing a compound of formula (I) and a pharmaceutically acceptable salt thereof, as well as its use as a drug, wherein the drug is a tyrosine kinase (i.e. VEGFR-2, C-RAF, B- RAF, and RET) inhibitors, and are useful in treating diseases associated with tyrosine kinase.

Formula (I)

Description

Urea-substituted aromatic ring-linked dioxazoline compound and preparation method and use thereof

The present disclosure relates to a urea-substituted aromatic ring-linked dioxinoquinoline compound, and a preparation method and use thereof, which belongs to the technical field of pharmaceutical chemistry.

VEGF (vascular endothelial growth factor) must be present for neovascularization and angiogenesis. During embryoogenesis, the formation of blood vessels is divided into two stages: neovascularization and angiogenesis. Neovascularization is the differentiation of primitive progenitor cells into endothelial cells; Angiogenesis is the outgrowth of nascent capillaries that occur in existing blood vessels in the form of budding. In normal adult mammals, there is only one type of angiogenesis, i.e., angiogenesis, which involves the breakdown of the local basement membrane around endothelial cells and invasion of the endothelial cells into the matrix. This invasion accompanies the proliferation of endothelial cells, forming a migration column of endothelial cells that change shape and form rings with each other. Thus, a new vascular cavity is formed.

VEGF is also essential for angiogenesis in tumor tissue, and vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptor 2 (VEGFR-2) signaling pathways play the most important role, the migration of endothelial cells in tumor tissue, It not only affects germination, survival, and proliferation, but also affects the permeability of tumor vessels. Endothelial cells without VEGF protein stimulation can also rely on autocrined VEGF protein to maintain integrity and survival. Vascular endothelial growth factor C (VEGFR-C)/vascular endothelial growth factor D (VEGF-D) mediates lymphangiogenesis in tumor tissue and promotes metastasis of tumor tissue. Therefore, the development of drugs targeting angiogenesis has become a hot spot.

Bevacizumab is a 93% humanized murine VEGF monoclonal antibody capable of binding to all subtypes of human VEGF A, blocks the VEGF/VEGFR signaling pathway, and inhibits tumor angiogenesis. . In 2004, bevacizumab (trade name Avastin) was approved by the FDA for sale in the United States, and is the first first-line drug for the treatment of metastatic colon cancer in combination with chemotherapy drugs. It has become an anti-tumor angiogenesis drug. Bevacizumab can improve abnormal tumor vessels, make them normal, and help chemotherapy drugs reach tumor tissue. Because of the mechanism of apoptosis induced by radiation therapy and chemotherapy, hypoxic partial pressure in tumor tissue induces the expression of VEGF, so the combination of bevacizumab and chemoradiotherapy drugs is a secondary response. Effectively prevent.

To date, there are 9 drugs targeting VEGFR-2/KDR: sorafenib, sunitinib, pazopanib, axitinib, vandetanib, and Lego. They are regorafenib, lenvatinib, nintedanib and cediranib (AZD2171), which have been approved by the FDA for the treatment of cancer.

Lenvatinib, the brand name Lenvima, is a drug for thyroid cancer developed by Eisai Corporation in Japan, has a specific inhibitory effect on VEGFR-1, VEGFR-2 and VEGFR-3, and also inhibits PDGFRβ and FGFR-1. . This is a class of TKIs that selectively target multiple receptors. With a mechanism similar to sorafenib, it directly inhibits tumor cell proliferation by inhibiting VEGFR-1, 2, 3 and PDGFR on the one hand, thereby inhibiting neovascularization, and FGFR-1 on the other hand. In 2015, the FDA approved Renbatinib for the treatment of thyroid cancer.

B-RAF is a type of tyrosine kinase receptor, and its abnormal activation plays an important role in the development and development of various malignancies. In most cases, abnormal activation of B-RAF is caused by genetic mutations. B-RAF belongs to the proto-oncogene. Studies have shown that more than 30 types of B-RAF gene mutations are associated with cancer, particularly the V600E gene mutation. Mutations in the B-RAF gene generally cause two diseases. First, mutations can be inherited and lead to birth defects. Second, an oncogene, an inherited mutation, can lead to cancer in the future. B-RAF gene mutations have been found in many cancerous tissues, including melanoma, colon cancer, thyroid cancer, non-small cell lung cancer, and glioma.

Sorafenib, under the trade name Nexavar, is a drug developed by Onyx Pharmaceuticals of the United States and Bayer AG of Germany, targeting the RAF/MEK/ERK signaling pathway, which mainly inhibits C-RAF and B-RAF, and also VEGFR -2, inhibits the activity of VEGFR-3, PDGFR-β, Flt-3 and c-Kit receptors. This can effectively inhibit tumor cell proliferation and angiogenesis in preclinical experiments. In a phase 3 clinical trial of metastatic renal cancer (renal cell carcinoma), sorafenib significantly increased the patient's overall survival rate. In July 2005, sorafenib was approved by the FDA as a drug for the treatment of advanced renal cell carcinoma.

There are many benefits of multi-target inhibitors similar to renbatinib and sorafenib, and research into these types of inhibitors is also a hot spot. However, at present, there are few similar drugs on the market, their solubility is limited, and drugs on the market suffer drug resistance and side effects. Therefore, these multi-target small molecule inhibitors will have a better therapeutic effect and application prospects compared to existing commercially available single-target inhibitors.

RET is also a type of transmembrane receptor tyrosine kinase, which is essential for the normal development of tissues such as the brain, nervous system, thyroid and lungs. Activating mutations and oncogenic fusions of receptor tyrosine kinase have been found in various tumor types including thyroid cancer, lung cancer, breast cancer and colon cancer. Currently, there are no commercially available drugs specifically targeting RET. Therefore, small molecule inhibitors for RET have very high application value.

In consideration of the drawbacks of the prior art, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof. Provides,

Formula (I)

In the above formula (I),

X is O or NH;

Y is CH;

Z is CH;

R ¹ is H; C ₁ -C ₉ alkyl; C ₃ -C ₇ cycloalkyl; 4 to 7 membered heterocyclyl; C ₁ -C ₆ alkyl substituted with C ₃ -C ₇ cycloalkyl; Or C ₁ -C ₆ alkyl substituted with 4 to 7 membered heterocyclyl; Or hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, unsubstituted amino, and mono- or di -C ₁ -C cost of one or more of the substituted amino-substituted C ₁ -C ₆ alkyl _{9 is} alkyl,

At this time, the 4 to 7 membered heterocyclyl is a 4 to 7 membered heterocyclyl containing 1 to 2 atoms selected from the group consisting of N, O, and S, and the heterocyclyl is unsubstituted or C ₁ Substituted with -C ₆ alkyl or C ₁ -C ₃ acyl, or oxidized with 1 to 2 oxygen atoms;

R ² is H or halogen;

R ³ is H or halogen;

R ⁴ is H or halogen;

R ⁵ is H; C ₁ -C ₉ alkyl; C ₃ -C ₈ cycloalkyl; C ₁ -C ₆ alkyl substituted with C ₃ -C ₈ cycloalkyl; Or unsubstituted aryl or heteroaryl; Or amino substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkyl, unsubstituted amino, halogen, trifluoromethyl , An aryl or heteroaryl group substituted with at least one of aryloxy and methylsulfonyl,

At this time, the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms, and contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S in the ring.

In an alternative embodiment, R ¹ is H; C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; 5 to 6 membered heterocyclyl; C ₁ -C ₃ alkyl substituted with C ₃ -C ₆ cycloalkyl; Or C ₁ -C ₃ alkyl substituted with 5 to 6 membered heterocyclyl; Or amino substituted with hydroxyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, unsubstituted amino, and mono- or di-C ₁ -C ₃ alkyl, and C ₁ substituted with one or more of -C ₆ alkyl,

At this time, the 5 to 6 membered heterocyclyl is a 5 to 6 membered heterocyclyl containing 1 to 2 atoms selected from the group consisting of N, O, and S, wherein the heterocyclyl is unsubstituted or C _1- Substituted with C ₃ alkyl or C ₁ -C ₃ acyl, or oxidized with 1 to 2 oxygen atoms.

In an alternative embodiment, R ¹ is selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydrofuran -3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyrrol-1-ylethyl, tetrahydropyrrol-1-yl Propyl, piperidin-1-ylethyl, piperidin-1-ylpropyl, piperazin-1-ylethyl, piperazin-1-ylpropyl, Morpholin-4-ylethyl, morpholin-4-ylpropyl, methylpiperazin-4-ylethyl, methylpiperazin-4-ylpropyl, N- Formylpiperazin-4-ylethyl (N-formylpiperazin-4-ylethyl), N-formylpiperazin-4-ylpropyl, N-acetylpiperazin-4-ylethyl (N-acetylpiperazin-4-ylethyl) , N-acetylpiperazin-4-ylpropyl, (1,1-dioxothiomorpholinyl)-4-ylethyl ((1,1-dioxothiomorpholin)-4-ylethyl), (1,1-dioxo Thiomorpholinyl)-4-ylpropyl, methylthioethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminoethyl, diethylaminopropyl, hydroxyethyl, hydroxypropyl, hydroxy Roxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl, aminopropyl, aminobutyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, (3S)-3-aminobutyl, ( 3R)-3-aminobutyl, (3S)-3-hydroxybutyl, or (3R)-3-hydroxybutyl.

In an alternative embodiment, R ¹ is selected from the group consisting of: butyl, isobutyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutyl Propyl, 4,4-dimethylpiperidin-1-ylethyl, 4,4-dimethylpiperidin-1-ylpropyl, dimethylaminopentyl, dimethylaminohexyl, and oxetan-3-yl.

In an alternative embodiment, the halogen of R ² , R ³ , and R ⁴ is F, Cl or Br.

In an alternative embodiment, R ⁵ is H; C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; C ₁ -C ₃ alkyl substituted with C ₃ -C ₆ cycloalkyl; Or unsubstituted aryl or heteroaryl; Or amino substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkyl, unsubstituted amino, halogen, trifluoromethyl , Aryloxy and methylsulfonyl substituted aryl or heteroaryl;

At this time, the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms, and contains 1 to 2 atoms selected from the group consisting of N, O, and S in the ring.

In an alternative embodiment, R ⁵ is H; C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; C ₁ -C ₃ alkyl substituted with C ₃ -C ₆ cycloalkyl; Or unsubstituted phenyl, naphthyl or heteroaryl; Or methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino , A phenyl, naphthyl, or heteroaryl group substituted with one or more of fluorine, chlorine, bromine, trifluoromethyl, phenoxy or methylsulfonyl;

At this time, the heteroaryl group is pyridinyl, pyrimidinyl, quinolinyl, quinazolinyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, And it is selected from the group consisting of pyrrolyl.

In an alternative embodiment, R ⁵ is selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-phenoxyphenyl, 3-(methylsulfonyl)phenyl, 4-(methylsulfonyl) Fonyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichloro Phenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro Ro-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-chlorophenyl, 3-fluoro Ro-4-chlorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4- (trifluoromethyl) phenyl, 2-chloro-5- (trifluoro Romethyl)phenyl, 3-chloro-4-(trifluoromethyl)phenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-4-chlorophenyl, 2-chloro -4-fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methoxy- Pyridin-4-yl, 3-methyl-isoxazol-5-yl, and naphthalen-1-yl.

In an alternative embodiment, R ⁵ is selected from the group consisting of: butyl, isobutyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-5-(trifluoromethyl)phenyl, 2-methyl -4-(trifluoromethyl)phenyl, 3-methyl-4-(trifluoromethyl)phenyl, 3-methyl-5-(trifluoromethyl)phenyl, 2-chloro-4-methylphenyl, 2-chloro -5-methylphenyl, and 3-chloro-4-methylphenyl.

The present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof,

Formula (I)

In the above formula (I),

X is O or NH;

Y is CH;

Z is CH;

R ¹ is 1 to 3 selected from the group consisting of C ₁ -C ₃ acyl, halogen, trifluoromethyl, cyano, -CONH ₂ , -NR ^a R ^b and a 4 to 7 membered heteroalicyclic group. C ₁ -C ₆ alkyl substituted with a substituent, wherein the 4 to 7 membered heteroalicyclic group is a 4 to 7 membered heteroali containing 1 to 2 atoms selected from the group consisting of N, O, and S as ring atoms As a cyclic group, the 4 to 7 membered heteroalicyclic group is substituted with 1 to 3 substituents selected from the group consisting of halogen, C ₁ -C ₃ alkyl, hydroxyl, -NH ₂ , and C ₁ -C ₃ acyl Become,

R ^a and R ^b are each independently -H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy substituted by a C ₁ -C ₆ alkyl, C ₁ -C ₃ alkylthio and a C ₁ -C ₆ alkyl, or substituted or unsubstituted amino-substituted amino substituted with C ₁ -C ₆ alkyl substituted with, where the substituted amino is mono- or di -C ₁ -C ₃ alkyl which is substituted by ;

R ² , R ³ , and R ⁴ are each independently H or halogen;

R ⁵ is H; C ₁ -C ₉ alkyl; C ₃ -C ₈ cycloalkyl; C ₁ -C ₆ alkyl substituted with C ₃ -C ₈ cycloalkyl; Unsubstituted aryl or heteroaryl; Or an aryl or heteroaryl group substituted with 1 to 3 substituents -B, wherein the substituents -B are each independently hydroxyl, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C _1- Amino substituted with C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkyl, unsubstituted amino, halogen, trifluoromethyl, aryloxy or methylsulfonyl;

At this time, the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms, and contains 1 to 3 atoms selected from the group consisting of N, O, and S in the ring.

Alternatively, R ¹ is -F, trifluoromethyl, cyano, -CONH ₂ , -NR ^a R ^b or C substituted with 1 to 3 substituents selected from the group consisting of 4 to 7 membered heteroalicyclic groups ₁ -C ₆ alkyl, wherein the 4 to 7 membered heteroalicyclic group is a 4 to 7 membered heteroalicyclic group containing 1 to 2 atoms selected from the group consisting of N, O, and S as ring atoms, The 4 to 7 membered heteroalicyclic group is substituted with 1 to 3 substituents selected from the group consisting of -F, C ₁ -C ₃ alkyl, hydroxyl, -NH ₂ , and C ₁ -C ₃ acyl,

R ^a and R ^b are each independently -H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl substituted with C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio and the C ₁ -C ₃ alkyl, or substituted or unsubstituted amino-substituted amino substituted with C ₁ -C ₃ alkyl substituted with, where the substituted amino is mono- or di -C ₁ -C ₃ alkyl which is substituted by .

R ⁵ is H; C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; C ₁ -C ₃ alkyl substituted with C ₃ -C ₆ cycloalkyl; Unsubstituted phenyl; Is naphthyl or heteroaryl; Or a phenyl, naphthyl or heteroaryl group substituted with 1 to 3 substituents -B, wherein the substituents -B are each independently methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopro Foxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, fluorine, chlorine, bromine, trifluoromethyl, phenoxy or methylsulfonyl;

At this time, the heteroaryl group is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, quinazolinyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, and pyrrolyl.

, 4-메틸-4-하이드록시피페리딘-1-일프로필, 4-메틸-4-하이드록시피페리딘-1-일에틸, 4-메틸-4-아미노피페리딘-1-일프로필, 4-메틸-4-아미노피페리딘-1-일에틸, 하이드록시에틸아미노에틸, 하이드록시프로필아미노에틸, 하이드록시에틸아미노프로필, 메톡시에틸아미노에틸, 메톡시프로필아미노에틸, 메톡시에틸아미노프로필, N-메틸-N-하이드록시에틸아미노에틸, N-메틸-N-하이드록시프로필아미노에틸, N-메틸-N-하이드록시에틸아미노프로필, N-메틸-N-메톡시에틸아미노에틸, N-메틸-N-메톡시프로필아미노에틸, N-메틸-N-메톡시에틸아미노프로필, N-메틸-N-사이클로부틸아미노프로필, N-메틸-N-사이클로프로필아미노프로필, N-메틸-N-사이클로펜틸아미노프로필, N-메틸-N-사이클로헥실아미노프로필, N-메틸-N-사이클로부틸아미노에틸, N-메틸-N-사이클로프로필아미노에틸, N-메틸-N-사이클로펜틸아미노에틸, 및 N-메틸-N-사이클로헥실미노에틸.Still alternatively, R ¹ is selected from the group consisting of: cyanomethyl, cyanoethyl, cyanopropyl, -CH ₂ CONH ₂ , -CH ₂ CF ₃ ,

, 4-methyl-4-hydroxypiperidin-1-ylpropyl, 4-methyl-4-hydroxypiperidin-1-ylethyl, 4-methyl-4-aminopiperidin-1-ylpropyl , 4-methyl-4-aminopiperidin-1-ylethyl, hydroxyethylaminoethyl, hydroxypropylaminoethyl, hydroxyethylaminopropyl, methoxyethylaminoethyl, methoxypropylaminoethyl, methoxyethyl Aminopropyl, N-methyl-N-hydroxyethylaminoethyl, N-methyl-N-hydroxypropylaminoethyl, N-methyl-N-hydroxyethylaminopropyl, N-methyl-N-methoxyethylaminoethyl , N-methyl-N-methoxypropylaminoethyl, N-methyl-N-methoxyethylaminopropyl, N-methyl-N-cyclobutylaminopropyl, N-methyl-N-cyclopropylaminopropyl, N-methyl -N-cyclopentylaminopropyl, N-methyl-N-cyclohexylaminopropyl, N-methyl-N-cyclobutylaminoethyl, N-methyl-N-cyclopropylaminoethyl, N-methyl-N-cyclopentylamino Ethyl, and N-methyl-N-cyclohexylminoethyl.

Still alternatively, R ⁵ is selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2 -Methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-phenoxyphenyl, 3-(methylsulfonyl)phenyl, 4-(methylsulfonyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl) Phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-chloro Phenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-(trifluoromethyl)phenyl, 2-chloro- 5-(trifluoromethyl)phenyl, 3-chloro-4-(trifluoromethyl)phenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-4-chloro Phenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methoxy-pyridin-4-yl, 3-methyl-isoxazol-5-yl, naphthalen-1-yl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-(trifluoromethyl) Phenyl, 2-methyl-4-(trifluoromethyl)phenyl, 3-methyl-4-(trifluoromethyl)phenyl, 2-methyl-5-(trifluoromethyl)phenyl, 2-chloro-4- Methylphenyl, 2-chloro-5-methylphenyl, and 3-chloro-4-methylphenyl.

The present disclosure also provides salts of compounds of formula (I), wherein said salts are acidic/anionic salts or basic/cationic salts; Pharmaceutically acceptable acidic/anionic salts are usually in the form of protonated basic nitrogen with an inorganic or organic acid; Representative organic or inorganic acids include: hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, glycolate, lactic acid, succinic acid, maleic acid, tartaric acid, malic acid, citric acid, fumaric acid, Gluconic acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, palmitic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, salicylic acid , Hexonic acid, trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, the following salts: aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium , Sodium and zinc.

In one aspect disclosed herein, a method for preparing a compound of formula (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof is provided,

The manufacturing method is

Reaction of the compound of formula (II) with H ₂ NR ⁵ to prepare a compound of formula (I):

(In the above formula X, Y, Z, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above)

Includes.

Unless otherwise specified, the following terms used in this application (including the specification and claims) have the definitions given below. In this application, the use of "or" or "and" means "and/or" unless otherwise specified. Further, the use of the terms "comprising" and other forms such as "including", "containing" and "having" is not limiting. Chapter titles used in this specification are for organizational purposes only and should not be construed as limitations on the described subject matter.

The term “substituted” as used herein refers to multiple substituents (eg, phenyl, aryl, heteroalkyl, heteroaryl), preferably 1 to 5 substituents, more preferably 1 to 3 substituents. , Most preferably contains 1 or 2 substituents, and is independently selected from the listed substituents.

Unless otherwise specified, alkyl includes saturated linear and branched hydrocarbon groups, and C ₁ -C ₉ indicates that the number of carbon atoms in the alkyl is 1-9.

Similarly, for example, C ₁ -C ₃ indicates that the number of carbon atoms in the alkyl is 1-3, for example, C ₁ -C ₆ alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl, etc. Include. The alkoxy group is an alkyl-O- group formed from the linear or branched alkyl group and -O- described above. Similarly, alkenyl and alkynyl groups include linear or branched alkenyl or alkynyl groups.

Cycloalkyl refers to a cyclic group formed by carbon atoms. For example, C ₃ -C ₇ cycloalkyl can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Similarly, cyclic alkenyl groups are included here.

The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted aromatic group, such as phenyl, naphthyl, anthracenyl.

“Oxidized by one or two oxygen atoms” means a sulfur atom oxidized by one oxygen atom to form a double bond between sulfur and oxygen, or a double bond between sulfur and two oxygen atoms. It refers to a sulfur atom oxidized by two oxygen atoms to form.

The term "heterocyclyl" as used herein, unless otherwise specified, is an unsubstituted or substituted stable 3-8 membered monocycle consisting of carbon atoms and 1 to 3 heteroatoms selected from N, O and S. Represents a click saturated ring system, wherein the N, S heteroatoms can be selectively oxidized and the N heteroatoms can also be optionally quaternized. Examples of such heterocyclyl rings include, but are not limited to: azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetra Hydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl ), dioxolanyl, dioxanyl, tetrahydroimidazolyl, tetrahydrooxazolyl, thiamorpholinyl sulfoxide, thiomorpholine sulfone sulfone) and oxadiazolyl.

The term "heteroaryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted stable 5 or 6 membered monocyclic aromatic ring system, and also 1 selected from carbon atoms and N, O, S It may represent an unsubstituted or substituted 9 or 10 membered benzo-fused heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of 3 heteroatoms, wherein N, S heteroatoms are optional Can be oxidized, and N heteroatoms can be optionally quaternized. Heteroaryl can be attached to any heteroatom or carbon atom to form a stable structure. Heteroaryl includes, but is not limited to: thienyl, furyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, heterogen. Sazolyl (isoxazolyl), pyranyl (pyranyl), pyridinyl (pyridinyl), piperazinyl (piperazinyl), pyrimidinyl (pyrimidinyl), pyrazinyl (pyrazinyl), pyridazinyl (pyridazinyl), pyrazolyl (pyrazolyl) , Thiadiazolyl, triazolyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, benzimidazolyl, benzopyu Ranil, benzothienyl, benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzothiadiazolyl, benzothiadiazolyl Zolyl (benzotriazolyl), adeninyl (adeninyl), quinolinyl (quinolinyl) or isoquinolinyl (isoquinolinyl).

The term "carbonyl" refers to the group -C(O)-.

Whenever the term “alkyl” or “aryl” or one of their prefix roots appears in the name of a substituent (eg, aralkyl, dialkylamino), it means that “alkyl” and It is to be construed as including those limitations given to “aryl”. The number of carbon atoms specified (e.g., C ₁ -C ₆ ) will independently represent the number of carbon atoms of the alkyl moiety or the alkyl moiety of a larger substituent, wherein the alkyl group is the root of the prefix.

It is clear that the compounds of formula (I), isomeric, crystalline or prodrugs, and pharmaceutically acceptable salts thereof, can exist in both solvated and unsolvated forms. For example, the solvated form may be a hydrate form. The present disclosure includes both solvated and unsolvated forms.

The compounds of the present disclosure may have asymmetric carbon atoms. These diastereomer mixtures can be separated into individual diastereomers based on their different physicochemical properties by methods known to those skilled in the art, for example by chromatography or fractional crystallization. have. Enantiomers convert the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound, separate the diastereoisomers, and convert the individual diastereomers into the corresponding pure enantiomers (e.g., hydrolysis ) Can be separated. All such isomers, including diastereomer mixtures and pure enantiomers, are considered part of the present disclosure.

As an active ingredient, the compound of the present disclosure and a method for preparing the same are all included in the present disclosure. In addition, crystalline forms of some compounds may exist as polymorphs, and such forms may also be included in the present disclosure. Additionally, some compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included within the scope of the present disclosure.

The compounds of the present disclosure may be used in free form for treatment, or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative for treatment. The term "pharmaceutically acceptable salt" as used herein refers to organic and inorganic salts of the compounds of the present disclosure, which are suitable and reasonable for use in humans and lower animals without excessive toxicity, irritation, allergic reactions, etc. It has an advantage/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in the art. Salts may be formed by reacting a compound of the present disclosure with a suitable free base or acid, including, but not limited to, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or acetic acid, oxalic acid, Salts of organic acids such as maleic acid, tartaric acid, citric acid, succinic acid and malonic acid. Alternatively, the salt can be obtained by methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate ( camphorate), camphorsulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphonate phosphate), gluconate, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate ), lauryl sulfate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate ( pectate), persulphate, per-3-phenylpropionate, phosphate, picrate, propionate, stearate, sulfate, thiocyanate ), p-toluenesulfonate, undecanoate, etc. Representative alkali metal salts or alkaline earth metal salts include salts such as sodium, lithium, potassium, calcium, and magnesium. Other pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed from halides, hydroxides, carboxylates, sulfates, phosphonates, nitrates, lower alkyl sulfonates and aryl sulfonates. Contains suitable non-toxic salts.

In addition, the term "prodrug" as used herein means that a compound can be converted into a compound of formula (I) of the present disclosure in vivo. These modifications are affected by the hydrolysis of prodrugs in the blood or enzymatic conversion of the parent compound in the blood or tissues.

Pharmaceutical compositions of the present disclosure include: a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof; Additional agents selected from kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer agents, anti-viral agents, anti-inflammatory agents, antifungal agents, antibiotics or anti-vascular hyper proliferation compounds; And any pharmaceutically acceptable carrier, adjuvant or vehicle.

The compounds of the present disclosure may be used alone, or may be used in combination with one or more other compounds of the present disclosure or one or more other agents. When administered in combination, the therapeutic agents may be formulated for simultaneous administration or sequential administration at different times, or the therapeutic agents may be administered in a single composition. "Combination therapy" refers to the use of a compound of the present disclosure in combination with other agents, in each case, for the purpose of achieving optimal results, wherein the co-administration of each agent or of each agent It is a form of sequential administration. Co-administration includes dosage forms for simultaneous delivery as well as individual dosage forms for each compound. Thus, administration of the compounds of the present disclosure can be combined with other treatments known in the art to improve symptoms of cancer, for example, radiation therapy or cytostatic agents used in the treatment of cancer. ), cytotoxic agents, and other anticancer agents. The order of administration is not limited in the present invention. The compounds of the present disclosure may be administered before, simultaneously or after other anticancer or cytotoxic agents.

In order to prepare the pharmaceutical ingredients of the present disclosure, one or more compounds of formula (I) or salts thereof may be directly mixed with a pharmaceutical carrier as an active ingredient, which is carried out according to conventional pharmaceutical formulation techniques. Carriers can be used in a wide variety of forms depending on the form of preparation designed for different modes of administration (eg oral or parenteral administration). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients jointly published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

The pharmaceutical compositions of the present disclosure may take the following forms: for example, in a form suitable for oral administration such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; Forms for parenteral injection such as clear solutions, suspensions, and emulsions; Or in forms for topical use such as ointments, creams; Or in the form of suppositories for rectal administration. The pharmaceutical ingredients may also be presented in unit dosage form for single administration at the correct dosage. The pharmaceutical ingredients will include conventional pharmaceutical carriers or excipients and compounds which are active ingredients prepared according to the present disclosure, and may also include other pharmaceutical or pharmaceutical preparations, carriers, adjuvants, and the like.

The therapeutic compound can also be administered to mammals other than humans. The drug dosage for mammals will depend on the species of the animal and its disease condition or disease condition. The therapeutic compound can be administered to the animal in the form of a capsule, bolus or tablet or liquid. The therapeutic compound can also be introduced into the animal by injection or infusion. These drug forms are manufactured in a traditional way that follows standard veterinary practice. Alternatively, the therapeutic compound may be mixed with an animal feed and supplied to the animal, so a concentrated feed additive or premix may be prepared by mixing a general animal feed.

A further object of the present disclosure is to provide a method of treating cancer in a subject in need thereof, including a method of administering to the subject a therapeutically effective amount of a composition containing a compound of the present disclosure.

The present disclosure also includes cancer (including non-solid tumors, solid tumors, primary or metastatic cancers as indicated elsewhere herein, and one or more other treatments for which the cancer is resistant or refractory. ) And other diseases (including, but not limited to, ocular fundus disease, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, etc. ) In the manufacture of a medicament for the treatment of), the use of a compound of the present disclosure or a pharmaceutically acceptable derivative thereof. Cancer includes, but is not limited to, any one of the following: non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma ), ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, stomach cancer, liver cancer, gastrointestinal tract Gastrointestinal stromal tumor, thyroid cancer, chronic granulocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer esophageal cancer), brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary cancer and sarcoma, and cholangiocarcinoma.

The present disclosure also provides a method for preparing the corresponding compound. Various synthetic methods can be used to prepare the compounds described herein, including the methods below. The compounds disclosed herein, or pharmaceutically acceptable salts, isomers, or hydrates thereof, can be prepared by using the methods below and synthetic methods known in the field of organic chemical synthesis, or by modifications of these methods as understood by those skilled in the art. Can be synthesized. Preferred methods include, but are not limited to, the following methods.

In one embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt, isomer or hydrate thereof, is prepared by the method below, wherein X is N or O, and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as described above,

The intermediate 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline (10-chloro-5-methoxy-2,3-dihydro-[ 1,4]dioxino[2,3-f]quinoline) was synthesized by a synthetic route in patent application CN201810160412X.

Reaction conditions:

In step 1), 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline is dissolved in an organic solvent and a Lewis acid is reacted to obtain 5- Hydroxy-10-chloro-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline is obtained, wherein the Lewis acid is boron tribromide or boron trichloride and the organic solvent is dichloromethane to be.

In step 2), 5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline is reacted with R ¹ X in an organic solvent to obtain formula III- A compound of A is obtained, wherein R ¹ is as previously defined; Organic solvents include, but are not limited to, one or a combination of two or more of tetrahydrofuran, dioxane, DMF, DMA, DMSO and acetonitrile; X of R ¹ X is chlorine, bromine, iodine, mesylate, p-toluene sulfonate or triflate.

In step 3), the compound of formula III-A is dissolved in an organic solvent, mixed with the compound of formula IV'-A, and heated to 100° C. to 140° C. to obtain a compound of formula III”; the organic solvent is toluene, chloro It is selected from the group consisting of one or a combination of two or more of benzene, xylene, DMF, DMA and DMSO.

In step 4), a nitro reduction reaction is carried out, which can usually be carried out by a person skilled in the art;

Preferably, the conditions of the nitro reduction reaction include, but are not limited to, hydrogen and Raney nickel, hydrogen and palladium/carbon, iron powder, zinc powder, and tin chloride.

In step 5), a compound of formula (II-A) is reacted with a compound of formula NH ₂ -R ⁵ in the presence of a condensing agent to obtain a compound of formula (IC);

Preferably, condensing agents include, but are not limited to, triphosgene, carbonyldiimidazole, phenyl chloroformate and phenyl p-nitrochloroformate;

The reaction can also be carried out in the presence of a base, the base being triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene (1,8 -diazabicycloundec-7-ene) and N-methylmorpholine, including, but not limited to, one or a combination of two or more; Aprotic solvents include, but are not limited to, one or a combination of two or more of dichloromethane, tetrahydrofuran, DMF, dioxane and dichloroethane.

Alternatively, step 5) is carried out in an aprotic solvent, wherein the aprotic solvent includes, but is not limited to, one and a combination of two or more of dichloromethane, tetrahydrofuran, DMF, dioxane and dichloroethane;

When R ¹ is -CH ₃ , steps 1) and 2) can be omitted, and the operation of step 3) can be performed directly. Meanwhile, the order of Step 1, Step 2, and Step 3 may not be fixed. For example, step 3 may be performed first, followed by steps 1 and 2.

In order to clarify the purpose, technical solutions, and advantages of the present disclosure, the present disclosure will be further described in more detail below along with specific embodiments. It is to be understood that the specific embodiments described herein are used only to illustrate the present disclosure and are not intended to limit the invention. If a specific technique or condition is not indicated in the examples, the product specification or technique or condition described in the literature in the art will be followed. If the reagent or instrument used does not indicate the manufacturer, these are all existing products on the market. The term “and/or” as used herein includes any and all combinations of one or more related listed items. The embodiments provided below may better explain the present disclosure. All temperatures are in degrees Celsius unless otherwise specified.

Example 1: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[ 2,3-f]quinolin-10-yl)oxy)phenyl)urea (1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-methoxy-2,3-dihydro-) Preparation of [1,4]dioxino[2,3-f]quinolin-10-yl)oxy)phenyl)urea)

Step 1): 10-Chloro-5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline (10-Chloro-5-methoxy-2,3-dihydro -[1,4]dioxino[2,3-f]quinoline) (251mg, 1mmol, see patent application CN201810160412X for synthetic route) and p-nitrophenol (139 mg, 1 mmol) in a reaction flask, followed by excitation Chlorobenzene was added. The mixture was heated to reflux while stirring until the reaction was complete. After cooling, the mixture was suction filtered. The resulting solid was washed with an aqueous potassium carbonate solution and 250 mg of a light yellow solid (5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4]dioxyno[2,3] -f]quinoline) was obtained in a yield of 71%. MS: 355 [M+H] ⁺ .

Step 2): The product (250 mg, 0.7 mmol) prepared in Step 1 was placed in a reaction flask, and then methanol and Raney nickel (250 mg) were added thereto. The reaction solution was stirred under a hydrogen atmosphere until the reaction was complete. The mixture was suction filtered and concentrated to give 226 mg of off-white solid product (4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f). ]Quinoline-10-yl)oxy)aniline) was obtained in 99% yield. MS: 325 [M+H] ⁺ .

Step 3): Triphosgene (296mg, 1mmol) is dissolved in tetrahydrofuran, followed by 4-chloro-3-(trifluoromethyl)aniline (195mg, 1mmol) and triethylamine (0.4mL). , 3mmol) was added. After stirring for 1 hour, a solution of the product of step 2 (226mg, 0.7mmol) and triethylamine (0.4mL, 3mmol) in tetrahydrofuran was added, followed by stirring until the reaction was completed. An aqueous solution of sodium carbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was concentrated and subjected to column chromatography to give 306 mg of white solid in 80% yield.

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.97 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.73-7.59 (m, 2H), 7.59-7.49 (m, 2H), 7.15-6.98 (m, 3H), 6.44 (d, J = 5.2 Hz, 1H), 4.34 (s, 4H), 3.93 (s, 3H); MS: 546 [M+H] ⁺ .

Example 2: 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-methoxy-2,3-dihydro-[1,4]dioxyno [2,3-f]quinolin-10-yl)oxy)phenyl)urea (1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-methoxy-2,3-dihydro -Preparation of [1,4]dioxino[2,3-f]quinolin-10-yl)oxy)phenyl)urea)

In step 3, the same as in Example 1 except that the same molar equivalent of 2-fluoro-5-(trifluoromethyl)aniline was used instead of 4-chloro-3-(trifluoromethyl)aniline. Preparation was carried out in a similar manner.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.26 (s, 1H), 8.90 (d, J = 2.9 Hz, 1H), 8.62 (dd, J = 7.4, 2.4 Hz, 1H), 8.42 (d, J = 5.2 Hz, 1H), 7.61-7.45 (m, 3H), 7.45-7.34 (m, 1H), 7.15-7.02 (m, 3H), 6.44 (d, J = 5.2 Hz, 1H), 4.39-4.27 (m, 4H), 3.92 (s, 3H). MS: 530 [M+H] ⁺ .

Example 2

Example 3

Example 3: 1-(4-fluorophenyl)-3-(4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-day)oxy)phenyl)urea

In step 3, preparation was carried out in a similar manner to Example 1, except that the same molar equivalent of p-fluoroaniline was used instead of 4-chloro-3-(trifluoromethyl)aniline.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.34 (d, J = 23.8 Hz, 2H), 8.40 (d, J = 5.2 Hz, 1H), 7.56 (dd, J = 8.9, 2.1 Hz, 2H) , 7.53-7.46 (m, 2H), 7.15-7.09 (m, 2H), 7.09-7.04 (m, 3H), 6.41 (d, J = 5.2 Hz, 1H), 4.42-4.28 (m, 4H), 3.92 (s, 3H). MS: 462 [M+H] ⁺ .

Example 4: 1-(2,4-difluorophenyl)-3-(4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f) ]Preparation of quinoline-10-yl)oxy)phenyl)urea

In step 3, preparation was carried out in a similar manner to Example 1, except that the same molar equivalent of 2,4-difluoroaniline was used instead of 4-chloro-3-(trifluoromethyl)aniline.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.19 (s, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.13-8.03 (m, 1H), 7.59-7.50 (m, 2H), 7.36-7.26 (m, 1H), 7.13-7.01 (m, 4H), 6.42 (d, J = 5.2 Hz, 1H), 4.38-4.30 (m, 4H) , 3.92 (s, 3H). MS: 480 [M+H] ⁺ .

Example 4

Example 5

Example 5: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-methoxy-2,3-dihydro-[1,4) ]Dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

In Step 1, preparation was carried out in a similar manner to Example 1, except that the same molar equivalent of 2-fluoro-4-nitrophenol was used instead of p-nitrophenol.

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 9.22 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.82-7.61 (m, 3H), 7.37-7.24 (m, 2H), 7.13 (s, 1H), 6.47 (d, J = 5.3 Hz, 1H), 4.41 (s, 4H), 3.98 (s, 3H) ; ¹³ CNMR (101 MHz, DMSO-d ₆ ) δ 161.1, 152.8, 152.5, 152.4, 149.6, 146.6, 139.5, 138.2, 138.2, 136.0, 132.4, 132.3, 123.8, 123.7, 123.0, 117.4, 115.7, 107.9, 107.7, 103.9, 101.5, 64.5, 63.9, 56.2, 49.0; MS: 564 [M+H] ⁺ .

Example 6: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-methoxy-2,3-dihydro-[1,4) ]Dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

In Step 1, preparation was carried out in a similar manner to Example 1, except that the same molar equivalent of 3-fluoro-4-nitrophenol was used instead of p-nitrophenol.

¹ HNMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.66 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.20-8.00 (m, 2H) , 7.62 (d, J = 1.5 Hz, 2H), 7.20-7.13 (m, 1H), 7.09 (s, 1H), 6.97-6.87 (m, 1H), 6.59 (d, J = 5.2 Hz, 1H), 4.52-4.18 (m, 4H), 3.93 (s, 3H); ¹³ CNMR (101 MHz, DMSO-d ₆ ) δ 160.4, 152.7, 152.4, 149.7, 146.8, 139.5, 138.0, 132.5, 132.3, 123.4, 123.1, 117.10, 116.1, 108.8, 108.3, 106.7, 101.6, 64.4, 63.9, 56.2, 40.2; MS: 564 [M+H] ⁺ .

Example 6

Example 7

Example 7: 1-(2-chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-cyclopropylurea

In step 1, preparation was carried out in a similar manner to Example 1, except that the same molar equivalent of 3-chloro-4-nitrophenol was used instead of p-nitrophenol.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.45 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.10-7.02 (m, 2H), 6.54-6.48 (m, 1H), 4.35-4.26 (m, 4H), 3.92 (s, 3H ), 2.60-2.52 (m, 1H), 0.70-0.61 (m, 2H), 0.46-0.38 (m, 2H). MS: 442 [M+H] ⁺ .

Example 8: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(2-methoxyethoxy)-2,3-dihydro-[1, 4] Preparation of dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Step 1): 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline (251mg, 1mmol) is dissolved in dichloromethane, followed by excitation To a solution of 1 mol/liter boron trichloride in dichloromethane (3 mL, 3 mmol) was added dropwise. The reaction solution was stirred until the reaction was complete. The mixture was concentrated to yield 236 mg of light yellow solid product (5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline) in 99% yield. Got into. MS: 238 [M+H] ⁺ .

Step 2): The product obtained in Step 1 (236 mg, 1 mmol) was dissolved in N,N-dimethylformamide, followed by 1-bromo-2-methoxyethane (138 mg, 1 mmol) and potassium carbonate (414 mg, 3mmol) was added. The mixture was heated while stirring until the reaction was complete. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was concentrated and then subjected to column chromatography to give 236 mg of off-white solid (10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxyno[ 2,3-f]quinoline) was obtained in 80% yield.

¹ H NMR (400 MHz, DMSO-d6) δ 8.70-8.46 (m, 1H), 7.50-7.33 (m, 1H), 7.25-7.09 (m, 1H), 4.40 (s, 4H), 4.30-4.23 ( m, 2H), 3.77-3.71 (m, 2H), 3.33-3.32 (m, 3H); MS: 296 [M+H] ⁺ .

Step 3-5): In step 3), the product prepared in step 2), (10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxyno The same molar equivalent of [2,3-f]quinoline) was added to 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxyno[2 in step 1) of Example 1 Steps 3)-5) were carried out in a similar manner to Example 1, except that ,3-f]quinoline was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.19 (s, 1H), 8.95 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.71-7.59 (m, 2H), 7.59-7.47 (m, 2H), 7.14-7.01 (m, 3H), 6.43 (d, J = 5.1 Hz, 1H), 4.40-4.29 (m, 4H), 4.25 (t, J = 4.3 Hz, 2H), 3.74 (t, J = 4.4 Hz, 2H), 3.35 (s, 3H). MS: 590 [M+H] ⁺ .

Example 9: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-ethoxy-2,3-dihydro-[1,4]dioxyno[ Preparation of 2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of iodoethane was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.14 (s, 1H), 8.89 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H) , 7.62-7.51 (m, 2H), 7.51-7.43 (m, 2H), 7.06-6.99 (m, 2H), 6.97 (s, 1H), 6.35 (d, J = 5.2 Hz, 1H), 4.33-4.19 (m, 4H), 4.11 (q, J = 6.9 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H). MS: 560 [M+H] ⁺ .

Example 9

Example 10

Example 10: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-isopropoxy-2,3-dihydro-[1,4]dioxyno Preparation of [2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of isopropyl bromide was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.17 (s, 1H), 8.93 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.73-7.47 (m, 4H), 7.16-6.92 (m, 3H), 6.42 (d, J = 5.2 Hz, 1H), 4.81 (p, J = 6.1 Hz, 1H), 4.38-4.21 (m, 4H) ), 1.36 (d, J = 6.0 Hz, 6H). MS: 574 [M+H] ⁺ .

Example 11: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-isobutoxy-2,3-dihydro-[1,4]dioxyno[ Preparation of 2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of isobutyl bromide was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.19 (s, 1H), 8.94 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.71-7.58 (m, 2H), 7.58-7.49 (m, 2H), 7.13-7.06 (m, 2H), 7.04 (s, 1H), 6.43 (d, J = 5.2 Hz, 1H), 4.40-4.28 (m, 4H), 3.90 (d, J = 6.5 Hz, 2H), 2.19-2.03 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H). MS: 588 [M+H] ⁺ .

Example 11

Example 12

Example 12: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(cyclopropylmethoxy)-2,3-dihydro-[1,4] Preparation of dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of bromomethylcyclopropane was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.12 (s, 1H), 8.88 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H) , 7.63-7.52 (m, 2H), 7.52-7.43 (m, 2H), 7.07-6.97 (m, 2H), 6.94 (s, 1H), 6.35 (d, J = 5.2 Hz, 1H), 4.33-4.21 (m, 4H), 3.90 (d, J = 7.0 Hz, 2H), 1.31-1.18 (m, 1H), 0.60-0.49 (m, 2H), 0.37-0.30 (m, 2H). MS: 586 [M+H] ⁺ .

Example 13: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(cyanomethoxy)-2,3-dihydro-[1,4]di Preparation of oxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of bromoacetonitrile was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.21 (s, 1H), 8.97 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H) , 7.69-7.59 (m, 2H), 7.59-7.51 (m, 2H), 7.26 (s, 1H), 7.15-7.07 (m, 2H), 6.48 (d, J = 5.2 Hz, 1H), 5.37 (s , 2H), 4.42-4.32 (m, 4H). MS: 571 [M+H] ⁺ .

Example 13

Example 14

Example 14: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(2-hydroxyethoxy)-2,3-dihydro-[1, 4] Preparation of dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of bromoethan-1-ol was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.18 (s, 1H), 8.94 (s, 1H), 8.41 (dd, J = 5.2, 1.7 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.73-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.16-7.01 (m, 3H), 6.43 (dd, J = 5.2, 1.8 Hz, 1H), 4.98-4.88 (m, 1H), 4.40-4.26 (m, 4H), 4.14 (t, J = 4.9 Hz, 2H), 3.85-3.72 (m, 2H). MS: 576 [M+H] ⁺ .

Example 15: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-hydroxypropoxy)-2,3-dihydro-[1, 4] Preparation of dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 3-bromopropan-1-ol was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.24 (s, 1H), 8.99 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H) , 7.70-7.58 (m, 2H), 7.58-7.51 (m, 2H), 7.14-7.02 (m, 3H), 6.42 (d, J = 5.2 Hz, 1H), 4.58 (t, J = 5.2 Hz, 1H ), 4.41-4.27 (m, 4H), 4.19 (t, J = 6.4 Hz, 2H), 3.66-3.54 (m, 2H), 1.95 (t, J = 6.3 Hz, 2H). MS: 590 [M+H] ⁺ .

Example 15

Example 16

Example 16: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-methoxypropoxy)-2,3-dihydro-[1, 4] Preparation of dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 1-bromo-3-methoxypropane was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8 .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.17 (s, 1H), 8.93 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H) , 7.72-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.13-7.06 (m, 2H), 7.04 (s, 1H), 6.43 (d, J = 5.2 Hz, 1H), 4.40-4.26 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.27 (s, 3H), 2.07-1.98 (m, 2H). MS: 604 [M+H] ⁺ .

Example 17: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(dimethylamino)propoxy)-2,3-dihydro-[ Preparation of 1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

A method similar to Example 8, except that the same molar equivalent of 3-chloro-N,N-dimethylpropan-1-amine hydrochloride was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8 Preparation was carried out.

¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.42 (d, J = 5.4 Hz, 1H), 8.08 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 8.7, 2.6 Hz, 1H) , 7.64-7.54 (m, 3H), 7.17-7.11 (m, 2H), 7.09 (s, 1H), 6.59 (d, J = 5.4 Hz, 1H), 4.49-4.39 (m, 4H), 4.29 (t , J = 6.0 Hz, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.50 (s, 6H), 2.26-2.15 (m, 2H). MS: 617[M+H] ⁺ .

Example 17

Example 18

Example 18: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(pyrrol-1-yl)propoxy)-2,3-di Preparation of hydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner as in Example 8, except that the same molar equivalent of 1-(3-chloropropyl)pyrrole hydrochloride was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8. .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.27 (s, 1H), 9.02 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.6 Hz, 1H) , 7.70-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.12-7.05 (m, 2H), 7.03 (d, J = 5.0 Hz, 1H), 6.42 (d, J = 5.2 Hz, 1H ), 4.39-4.27 (m, 4H), 4.20-4.11 (m, 2H), 2.58-2.54 (m, 2H), 2.48-2.42 (m, 4H), 2.00-1.92 (m, 2H), 1.75-1.64 (m, 4H). MS: 643 [M+H] ⁺ .

Example 19: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(piperidin-1-yl)propoxy)-2,3 Preparation of -dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner as in Example 8, except that the same molar equivalent of 1-(3-chloropropyl)piperidine hydrochloride was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8. Performed.

¹ H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.67 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 8.15 (d, J = 2.6 Hz, 1H), 7.70 (dd, J = 8.8, 2.6 Hz, 1H), 7.64-7.55 (m, 3H), 7.13-6.99 (m, 3H), 6.42 (d, J = 5.2 Hz, 1H) , 4.42-4.25 (m, 4H), 4.16 (t, J = 6.4 Hz, 2H), 3.35-3.21 (m, 4H), 2.57 (t, J = 7.3 Hz, 2H), 1.99 (t, J = 7.0 Hz, 2H), 1.62-1.49 (m, 4H), 1.47-1.35 (m, 2H).. MS: 657 [M+H] ⁺ .

Example 19

Example 20

Example 20: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1 Preparation of ,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner as in Example 8 except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8 I did.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.22 (s, 1H), 8.97 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.70-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.14-6.99 (m, 3H), 6.43 (d, J = 5.2 Hz, 1H), 4.39-4.26 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.38-3.23 (m, 4H), 2.49-2.28 (m, 6H), 2.05-1.88 (m, 2H). MS: 659 [M+H] ⁺ .

Example 21: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(4-methylpiperazin-1-yl)propoxy)-2 Preparation of ,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

A method similar to Example 8, except that the same molar equivalent of 1-(3-chloropropyl)-4-methylpiperazine hydrochloride was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8 Preparation was carried out.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.20 (s, 1H), 8.95 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H) , 7.70-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.14-7.05 (m, 2H), 7.03 (s, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.38-4.27 (m, 4H), 4.15 (t, J = 6.4 Hz, 2H), 2.50-2.49 (m, 2H), 2.45 (t, J = 7.2 Hz, 2H), 2.43-2.20 (m, 6H), 2.15 ( s, 3H), 1.99-1.90 (m, 2H). MS: 672 [M+H] ⁺ .

Example 21

Example 22

Example 22: 1-(4-((5-(3-(4-acetylpiperazin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxyno[2,3 Preparation of -f]quinolin-10-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea

Using the same molar equivalent of 1-(4-(3-chloropropyl)piperazin-1-yl)ethan-1-one hydrochloride instead of 1-bromo-2-methoxyethane in step 2) of Example 8 Preparation was carried out in a similar manner to Example 8 except that.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.20 (s, 1H), 8.95 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.70-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.14-7.02 (m, 3H), 6.42 (d, J = 5.2 Hz, 1H), 4.39-4.28 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.48-3.38 (m, 4H), 2.49-2.47 (m, 2H), 2.45-2.37 (m, 2H), 2.34 (t, J = 5.1 Hz, 2H), 2.03-1.93 (m, 5H). MS: 700 [M+H] ⁺ .

Example 23: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(1,1-dioxothiomorpholino)propoxy)- Preparation of 2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Example 8, except that the same molar equivalent of 4-(3-chloropropyl)thiomorpholine-1,1-dioxide hydrochloride was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8 Preparation was carried out in a similar manner to.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.21 (s, 1H), 8.96 (s, 1H), 8.41 (d, J = 5.3 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.70-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.13-7.04 (m, 3H), 6.42 (d, J = 5.2 Hz, 1H), 4.39-4.27 (m, 4H), 4.18 (t, J = 6.4 Hz, 2H), 3.16-3.06 (m, 4H), 2.98-2.87 (m, 4H), 2.71-2.61 (m, 2H), 2.03-1.89 (m, 2H). MS: 707 [M+H] ⁺ .

Example 23

Example 24

Example 24: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(4,4-dimethylpiperidin-1-yl)propoxy )-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Example 8, except that the same molar equivalent of 1-(3-chloropropyl)-4,4-dimethylpiperidine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8 Preparation was carried out in a similar manner to.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.21 (s, 1H), 8.97 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.69-7.58 (m, 2H), 7.58-7.49 (m, 2H), 7.13-7.06 (m, 2H), 7.04 (s, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.40-4.26 (m, 4H), 4.15 (t, J = 6.4 Hz, 2H), 2.48-2.42 (m, 2H), 2.41-2.29 (m, 4H), 2.02-1.89 (m, 2H), 1.33 (t, J = 5.6 Hz, 4H), 0.89 (s, 6H). MS: 685 [M+H] ⁺ .

Example 25: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(4-hydroxy-4-methylpiperidin-1-yl) )Propoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Example except that the same molar equivalent of 1-(3-chloropropyl)-4-methylpiperidin-4-ol was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8 Preparation was carried out in a similar manner to 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.29 (s, 1H), 9.03 (s, 1H), 8.40 (d, J = 5.3 Hz, 1H), 8.18-8.06 (m, 1H), 7.68- 7.58 (m, 2H), 7.55 (d, J = 8.9 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 7.03 (s, 1H), 6.42 (d, J = 5.3 Hz, 1H), 4.33 (dd, J = 10.6, 4.9 Hz, 4H), 4.20-4.11 (m, 2H), 2.60-2.57 (m, 1H), 2.46-2.35 (m, 6H), 1.99-1.92 (m, 2H), 1.52-1.44 (m, 4H), 1.12-1.05 (m, 3H). MS: 687 [M+H] ⁺ .

Example 26: 1-(4-((5-(3-(4-amino-4-methylpiperidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxy Preparation of no[2,3-f]quinolin-10-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea

1) Step 1-5: tert-butyl (1-(3-((10-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-2, Preparation of 3-dihydro-[1,4]dioxyno[2,3-f]quinolin-5-yl)oxy)propyl)-4-methylpiperazin-4-yl)carbamate

The same molar equivalent of tert-butyl (1-(3-chloropropyl)-4-methylpiperidin-4-yl)carbamate was substituted for 1-bromo-2-methoxyethane in step 2) of Example 8 Preparation was carried out in a similar manner to Example 8 except that it was used. MS: 786 [M+H] ⁺ .

2) Step 6: The final product (79mg, 1mmol) obtained in steps 1-5 above was dissolved in dichloromethane (3mL), and then trifluoroacetic acid (1mL) was added dropwise thereto. The mixture was reacted for 3 hours. The reaction was quenched at 0° C. with a solution of ammonia in methanol. The reaction solution was evaporated to dryness and purified by column chromatography to obtain 20 mg of a white solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.26 (s, 1H), 9.01 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H) , 7.71-7.58 (m, 2H), 7.58-7.48 (m, 2H), 7.14-7.05 (m, 2H), 7.03 (s, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.39-4.28 (m, 4H), 4.15 (t, J = 6.4 Hz, 2H), 2.46 (t, J = 7.1 Hz, 2H), 2.43-2.28 (m, 4H), 1.99-1.87 (m, 2H), 1.78- 1.47 (m, 2H), 1.47-1.30 (m, 4H), 1.01 (s, 3H). MS: 686 [M+H] ⁺ .

Example 27: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-((2-methoxyethyl)(methyl)amino)propoxy) Preparation of -2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

1) Step 1-5): 1-(4-((5-(3-bromopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenylurea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 1,3-dibromopropane was used instead of the iodoethane in step 2) of Example 8. MS: 652 [M+H] ⁺ .

2) Step 6: The product obtained in step 1-5) (1-(4-((5-(3-bromopropoxy)-2,3-dihydro-[1,4]dioxyno[2, 3-f]quinolin-10-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenylurea) (65mg, 1mmol) was dissolved in acetonitrile (3mL), then Triethylamine (202mg, 2mmol) and 2-methoxy-N-methylethan-1-amine (135 mg, 1.5 mmol) were added thereto, and the mixture was reacted for 3 hours at 25° C. The reaction solution was dried. And subjected to column chromatography to give 20 mg of a white solid.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.31-9.23 (m, 1H), 9.05-8.96 (m, 1H), 8.43-8.35 (m, 1H), 8.15-8.07 (m, 1H), 7.69 -7.57 (m, 2H), 7.57-7.49 (m, 2H), 7.12-7.04 (m, 2H), 7.04-6.99 (m, 1H), 6.46-6.37 (m, 1H), 4.38-4.27 (m, 4H), 4.20-4.08 (m, 2H), 3.43-3.39 (m, 2H), 3.30 (s, 3H), 3.21 (s, 3H), 2.55-2.52 (m, 2H), 2.25-2.21 (m, 2H), 1.99-1.86 (m, 2H). MS: 661 [M+H] ⁺ .

Example 28: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(cyclobutyl)(methyl)amino)propoxy)-2,3 Preparation of -dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 27, except that the same molar equivalent of N-methylcyclobutylamine was used instead of 2-methoxy-N-methylethan-1-amine in step 6) of Example 27.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.04-9.79 (m, 1H), 9.74-9.52 (m, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.29 (d, J = 16.4 Hz, 1H), 8.15 (d, J = 2.7 Hz, 1H), 7.69 (dd, J = 8.9, 3.0 Hz, 1H), 7.64-7.54 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H ), 7.05 (s, 1H), 6.41 (d, J = 5.2 Hz, 1H), 4.33 (s, 4H), 4.16 (t, J = 6.5 Hz, 2H), 3.00-2.86 (m, 1H), 2.50 -2.42 (m, 2H), 2.22-2.11 (m, 3H), 2.06-1.97 (m, 2H), 1.97-1.89 (m, 2H), 1.88-1.75 (m, 2H), 1.68-1.53 (m, 2H). MS: 657 [M+H] ⁺ .

Example 28

Example 29

Example 29: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-((6-methoxyhexyl)oxy)-2,3-dihydro-[ Preparation of 1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 1-chloro-6-methoxyhexane was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.20 (d, J = 4.0 Hz, 1H), 8.95 (s, 1H), 8.45-8.38 (m, 1H), 8.12 (d, J = 4.0 Hz, 1H), 7.69-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.13-7.05 (m, 2H), 7.04 (d, J = 4.1 Hz, 1H), 6.45-6.38 (m, 1H) , 4.37-4.29 (m, 4H), 4.14-4.08 (m, 2H), 3.22 (s, 3H), 2.57-2.53 (m, 2H), 1.84-1.72 (m, 2H), 1.57-1.50 (m, 2H), 1.50-1.42 (m, 2H), 1.42-1.31 (m, 2H). MS: 646 [M+H] ⁺ .

Example 30: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-((6-(dimethylamino)hexyl)oxy)-2,3-dihydro Preparation of -[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

In a similar method to Example 8, except that the same molar equivalent of 6-chloro-N,N-dimethylhexan-1-amine was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8 Preparation was carried out.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.32 (d, J = 6.1 Hz, 1H), 9.07 (d, J = 6.1 Hz, 1H), 8.43-8.34 (m, 1H), 8.17-8.06 ( m, 1H), 7.70-7.58 (m, 2H), 7.58-7.48 (m, 2H), 7.12-6.98 (m, 3H), 6.45-6.35 (m, 1H), 4.38-4.26 (m, 4H), 4.16-4.04 (m, 2H), 2.35-2.25 (m, 2H), 2.20 (s, 6H), 1.85-1.72 (m, 2H), 1.52-1.40 (m, 4H), 1.40-1.29 (m, 2H) ). MS: 659 [M+H] ⁺ .

Example 30

Example 31

Example 31: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(oxetan-3-yl)oxy)-2,3-dihydro-[ Preparation of 1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of oxetan-3-yl 4-methylbenzenesulfonate was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8. Performed.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.21 (s, 1H), 8.97 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.72-7.59 (m, 2H), 7.59-7.49 (m, 2H), 7.14-7.04 (m, 2H), 6.68 (s, 1H), 6.44 (d, J = 5.2 Hz, 1H), 5.52-5.39 (m, 1H), 5.08-4.96 (m, 2H), 4.68-4.58 (m, 2H), 4.44-4.30 (m, 4H). MS: 588 [M+H] ⁺ .

Example 32: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro Preparation of -[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation in a similar manner to Example 8, except that the same molar equivalent of tetrahydrofuran-3-yl 4-methylbenzenesulfonate was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8 Was performed.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.19 (s, 1H), 8.95 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.69-7.58 (m, 2H), 7.58-7.51 (m, 2H), 7.12-7.06 (m, 2H), 7.02 (s, 1H), 6.43 (d, J = 5.2 Hz, 1H), 5.24-5.16 (m, 1H), 4.38-4.28 (m, 4H), 4.01-3.93 (m, 1H), 3.93-3.83 (m, 2H), 3.83-3.73 (m, 1H), 2.39-2.27 (m, 1H) , 2.13-2.00 (m, 1H). MS: 602 [M+H] ⁺ .

Example 32

Example 33

Example 33: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-((tetraharidro-2H-pyran-4-yl)oxy)-2, Preparation of 3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Similar to Example 8, except that the same molar equivalent of tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8 Preparation was carried out by the method.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.20 (s, 1H), 8.95 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) , 7.70-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.16 (s, 1H), 7.11-7.05 (m, 2H), 6.42 (d, J = 5.2 Hz, 1H), 4.85-4.74 (m, 1H), 4.38-4.27 (m, 4H), 3.95-3.84 (m, 2H), 3.63-3.49 (m, 2H), 2.14-2.00 (m, 2H), 1.74-1.58 (m, 2H) . MS: 616 [M+H] ⁺ .

Example 34: 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(2-methoxyethoxy)-2,3-dihydro-[1 Preparation of ,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

As in Example 8, except that the same molar equivalent of 2-fluoro-5-(trifluoromethyl)aniline was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out in a similar manner.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.33 (s, 1H), 8.96 (d, J = 2.9 Hz, 1H), 8.62 (dd, J = 7.3, 2.3 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.60-7.45 (m, 3H), 7.44-7.35 (m, 1H), 7.15-7.03 (m, 3H), 6.43 (d, J = 5.2 Hz, 1H), 4.39-4.29 (m, 4H), 4.29-4.20 (m, 2H), 3.78-3.70 (m, 2H), 3.30 (s, 3H). MS: 574 [M+H] ⁺ .

Example 34

Example 35

Example 35: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-ethoxy-2,3-dihydro-[1,4]dioxyno[ Preparation of 2,3-f]quinolin-10-yl)oxy)-2-fluorophenyl)urea

The same molar equivalent of iodoethane was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-fluoro-4-nitrophenol was used in step 3 of Example 8. Preparation was carried out in a similar manner as in Example 8, except that) of p-nitrophenol was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.52 (s, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 5.1 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 8.09-8.00 (m, 1H), 7.62 (d, J = 1.6 Hz, 2H), 7.16 (dd, J = 11.8, 2.7 Hz, 1H), 7.06 (s, 1H), 6.95- 6.88 (m, 1H), 6.57 (d, J = 5.1 Hz, 1H), 4.38-4.24 (m, 4H), 4.18 (q, J = 6.9 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H ). MS: 578 [M+H] ⁺ .

Example 36: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(2-methoxyethoxy)-2,3-di Preparation of hydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 2-fluoro-4-nitrophenol was used instead of 1 p-nitrophenol in step 3) of Example 8.

¹ HNMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.22 (s, 1H), 8.42 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.77 -7.52 (m, 3H), 7.25 (d, J = 2.5 Hz, 2H), 7.12-7.04 (m, 1H), 6.47-6.35 (m, 1H), 4.47-4.32 (m, 4H), 4.30-4.19 (m, 2H), 3.80-3.69 (m, 2H), 3.35 (s, 3H); MS: 608 [M+H] ⁺ .

Example 36

Example 37

Example 37: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(2-methoxyethoxy)-2,3-di Preparation of hydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in the same manner as in Example 8, except that the same molar equivalent of 3-fluoro-4-nitrophenol was used instead of p-nitrophenol in step 3) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.61 (s, 1H), 8.72 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 11.9 Hz, 1H) , 8.10-8.01 (m, 1H), 7.62 (s, 2H), 7.17 (dd, J = 11.8, 2.7 Hz, 1H), 7.09 (s, 1H), 6.92 (d, J = 9.1 Hz, 1H), 6.57 (d, J = 5.2 Hz, 1H), 4.40-4.19 (m, 6H), 3.74 (t, J = 4.3 Hz, 2H), 3.34 (s, 3H). MS: 608 [M+H] ⁺ .

Example 38: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(3-methoxypropoxy)-2,3-di Preparation of hydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 1-bromo-3-methoxypropane was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 2-fluoro-4-nitrophenol Preparation was carried out in a similar manner as in Example 8, except that the p-nitrophenol of step 3) of Example 8 was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.37 (s, 1H), 9.26 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H) , 7.75-7.59 (m, 3H), 7.30-7.22 (m, 2H), 7.05 (s, 1H), 6.41 (dd, J = 5.2, 1.1 Hz, 1H), 4.42-4.31 (m, 4H), 4.18 (t, J = 6.4 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.27 (s, 3H), 2.11-1.96 (m, 2H). MS: 622 [M+H] ⁺ .

Example 38

Example 39

Example 39: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(3-methoxypropoxy)-2,3-di Preparation of hydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 1-bromo-3-methoxypropane was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-fluoro-4-nitrophenol Preparation was carried out in a similar manner as in Example 8, except that the p-nitrophenol of step 3) of Example 8 was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.69 (s, 1H), 8.84 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H) , 8.08-8.00 (m, 1H), 7.63 (d, J = 2.2 Hz, 2H), 7.15 (dd, J = 11.8, 2.7 Hz, 1H), 7.07 (s, 1H), 6.95-6.87 (m, 1H) ), 6.58 (d, J = 5.1 Hz, 1H), 4.37-4.25 (m, 4H), 4.18 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 6.3 Hz, 2H), 3.27 (s , 3H), 2.08-1.97 (m, 2H). MS: 622 [M+H] ⁺ .

Example 40: 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-methoxypropoxy)-2,3-dihydro-[1 Preparation of ,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 1-bromo-3-methoxypropane was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and 2-fluoro-5-(trifluoromethyl) Preparation was carried out in a similar manner as in Example 8, except that the same molar equivalent of aniline was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.26 (s, 1H), 8.90 (d, J = 2.9 Hz, 1H), 8.62 (dd, J = 7.3, 2.4 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.62-7.44 (m, 3H), 7.44-7.33 (m, 1H), 7.14-7.06 (m, 2H), 7.04 (s, 1H), 6.43 (d, J = 5.2 Hz , 1H), 4.40-4.27 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 6.3 Hz, 2H), 3.27 (s, 3H), 2.10-1.99 (m, 2H). MS: 588 [M+H] ⁺ .

Example 40

Example 41

Example 41: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(3-morpholinopropoxy)-2,3- Preparation of dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same mole of 2-fluoro-4-nitrophenol Preparation was carried out in a similar manner as in Example 8, except that the equivalent was used instead of p-nitrophenol in step 3) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.30 (s, 1H), 9.20 (s, 1H), 8.41 (d, J = 5.3 Hz, 1H), 8.17-8.07 (m, 1H), 7.76- 7.58 (m, 3H), 7.29-7.21 (m, 2H), 7.07 (s, 1H), 6.41 (dd, J = 5.2, 1.0 Hz, 1H), 4.40-4.33 (m, 4H), 4.19 (t, J = 6.3 Hz, 2H), 3.68-3.58 (m, 4H), 3.34-3.32 (m, 4H), 2.63-2.53 (m, 2H), 2.07-1.95 (m, 2H). MS: 677 [M+H] ⁺ .

Example 42: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(3-morpholinopropoxy)-2,3- Preparation of dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same mole of 3-fluoro-4-nitrophenol Preparation was carried out in a similar manner as in Example 8, except that the equivalent was used instead of p-nitrophenol in step 3) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.49 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.16-8.10 (m, 1H), 8.10-8.02 (m, 1H), 7.66-7.57 (m, 2H), 7.16 (dd, J = 11.8, 2.7 Hz, 1H), 7.10 (s, 1H), 6.94-6.87 (m, 1H) , 6.59 (d, J = 5.2 Hz, 1H), 4.37-4.26 (m, 4H), 4.21 (t, J = 6.2 Hz, 2H), 3.84-3.52 (m, 4H), 3.12-2.51 (m, 6H) ), 2.20-1.98 (m, 2H). MS: 677 [M+H] ⁺ .

Example 42

Example 43

Example 43: 1-(2-chloro-4-((5-ethoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-cyclopropylurea

The same molar equivalent of iodoethane was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used in step 3 of Example 8). A method similar to Example 8 except that p-nitrophenol of was used instead of and the same molar equivalent of cyclopropylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.09-7.01 (m, 2H), 6.50 (d, J = 5.2 Hz, 1H), 4.38-4.26 (m, 4H), 4.18 ( q, J = 7.0 Hz, 2H), 2.59-2.53 (m, 1H), 1.41 (t, J = 7.0 Hz, 3H), 0.70-0.60 (m, 2H), 0.44-0.37 (m, 2H). MS: 456 [M+H] ⁺ .

Example 44: 1-(2-Chloro-4-((5-isopropoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy )Phenyl)-3-cyclopropylurea

The same molar equivalent of isopropyl bromide was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used in step 3 of Example 8). A method similar to Example 8 except that p-nitrophenol of was used instead of and the same molar equivalent of cyclopropylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.43 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.90 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 3.0 Hz, 1H), 7.09-7.00 (m, 2H), 6.50 (d, J = 5.2 Hz, 1H), 4.81 (p, J = 6.0 Hz, 1H) , 4.36-4.24 (m, 4H), 2.60-2.52 (m, 1H), 1.36 (d, J = 6.0 Hz, 6H), 0.71-0.60 (m, 2H), 0.46-0.36 (m, 2H). MS: 470 [M+H] ⁺ .

Example 44

Example 45

Example 45: 1-(2-chloro-4-((5-isobutoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-cyclopropylurea

The same molar equivalent of isobutyl bromide was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used in step 3 of Example 8). A method similar to Example 8 except that p-nitrophenol of was used instead of and the same molar equivalent of cyclopropylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.90 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 2.9 Hz, 1H), 7.07-7.01 (m, 2H), 6.51 (d, J = 5.2 Hz, 1H), 4.36-4.26 (m, 4H), 3.90 ( d, J = 6.6 Hz, 2H), 2.57-2.55 (m, 1H), 2.16-2.05 (m, 1H), 1.03 (d, J = 6.7 Hz, 6H), 0.69-0.63 (m, 2H), 0.46 -0.38 (m, 2H). MS: 484 [M+H] ⁺ .

Example 46: 1-(2-chloro-4-((5-(cyclopropylmethoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10- Preparation of yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of bromomethylcyclopropane was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used in the step of Example 8. As in Example 8, except that it was used instead of p-nitrophenol in 3), and the same molar equivalent of cyclopropylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out in a similar manner.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.89 (s, 1H), 7.24 (d, J = 2.7 Hz, 1H), 7.13 (d, J = 2.9 Hz, 1H), 7.09-6.98 (m, 2H), 6.51 (d, J = 5.1 Hz, 1H), 4.39-4.24 (m, 4H), 3.97 ( d, J = 7.0 Hz, 2H), 2.62-2.54 (m, 1H), 1.38-1.20 (m, 1H), 0.73-0.57 (m, 4H), 0.48-0.33 (m, 4H). MS: 482 [M+H] ⁺ .

Example 46

Example 47

Example 47: 1-(2-Chloro-4-((5-(cyanomethoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl )Oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of bromoacetonitrile was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used in the step of Example 8. As in Example 8, except that it was used instead of p-nitrophenol in 3), and the same molar equivalent of cyclopropylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out in a similar manner.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.50 (dd, J = 5.2, 1.8 Hz, 1H), 8.19 (dd, J = 9.0, 1.8 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.31-7.24 (m, 2H), 7.15 (d, J = 2.9 Hz, 1H), 7.10-7.05 (m, 1H), 6.57 (dd, J = 5.2, 1.8 Hz, 1H), 5.37 (s , 2H), 4.40-4.31 (m, 4H), 2.58-2.55 (m, 1H), 0.70-0.62 (m, 2H), 0.47-0.37 (m, 2H). MS: 467 [M+H] ⁺ .

Example 48: 1-(2-Chloro-4-((5-(2-hydroxyethoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 2-bromoethan-1-ol was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was carried out. Except that it was used instead of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out in a similar manner as in Example 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 2.9 Hz, 1H), 7.10-7.02 (m, 2H), 6.51 (d, J = 5.1 Hz, 1H), 4.94 (t, J = 5.4 Hz, 1H) , 4.37-4.27 (m, 4H), 4.14 (t, J = 4.9 Hz, 2H), 3.83-3.76 (m, 2H), 2.60-2.53 (m, 1H), 0.68-0.61 (m, 2H), 0.44 -0.38 (m, 2H). MS: 472 [M+H] ⁺ .

Example 48

Example 49

Example 49: 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in step 5) of Example 8. Preparation was carried out in a similar manner as in Example 8, except that -(trifluoromethyl)aniline was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.10-7.02 (m, 2H), 6.51 (d, J = 5.2 Hz, 1H), 4.38-4.27 (m, 4H), 4.27- 4.20 (m, 2H), 3.77-3.67 (m, 2H), 3.34 (s, 3H), 2.61-2.53 (m, 1H), 0.79-0.55 (m, 2H), 0.52-0.28 (m, 2H). MS: 486 [M+H] ⁺ .

Example 50: 1-(2-Chloro-4-((5-(3-hydroxypropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 3-bromopropan-1-ol was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used. Except that it was used instead of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out in a similar manner as in Example 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.90 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 2.9 Hz, 1H), 7.08-7.02 (m, 2H), 6.51 (d, J = 5.2 Hz, 1H), 4.63-4.57 (m, 1H), 4.35- 4.27 (m, 4H), 4.19 (t, J = 6.4 Hz, 2H), 3.64-3.57 (m, 2H), 2.59-2.54 (m, 1H), 1.94 (t, J = 6.3 Hz, 2H), 0.69 -0.62 (m, 2H), 0.45-0.38 (m, 2H). MS: 486 [M+H] ⁺ .

Example 50

Example 51

Example 51: 1-(2-Chloro-4-((5-(3-methoxypropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 1-bromo-3-methoxypropane was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used. Except that it was used instead of p-nitrophenol of step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline of step 5) of Example 8 Was carried out in a similar manner to Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.08-7.01 (m, 2H), 6.51 (d, J = 5.2 Hz, 1H), 4.37-4.25 (m, 4H), 4.17 ( t, J = 6.4 Hz, 2H), 3.51 (t, J = 6.3 Hz, 2H), 3.27 (s, 3H), 2.59-2.54 (m, 1H), 2.09-2.01 (m, 2H), 0.71-0.58 (m, 2H), 0.47-0.37 (m, 2H). MS: 500 [M+H] ⁺ .

Example 52: 1-(2-chloro-4-((5-(3-(dimethylamino)propoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f] Preparation of quinoline-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 3-chloro-N,N-dimethylpropan-1-amine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and 3-chloro-4-nitrophenol The same molar equivalent of is used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine is used in step 5) of Example 8, 4-chloro-3-(trifluoromethyl)aniline. Preparation was carried out in a similar manner as in Example 8, except that it was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.90 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 2.9 Hz, 1H), 7.07-7.02 (m, 2H), 6.51 (d, J = 5.1 Hz, 1H), 4.36-4.27 (m, 4H), 4.15 ( t, J = 6.5 Hz, 2H), 2.57-2.55 (m, 1H), 2.40 (t, J = 7.1 Hz, 2H), 2.17 (s, 6H), 1.96-1.89 (m, 2H), 0.70-0.62 (m, 2H), 0.49-0.39 (m, 2H). MS: 513 [M+H] ⁺ .

Example 52

Example 53

Example 53: 1-(2-chloro-4-((5-(3-(pyrrol-1-yl)propoxy)-2,3-dihydro-[1,4]dioxyno[2,3] Preparation of -f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 1-(3-chloropropyl)pyrrole hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used. Except that it was used instead of p-nitrophenol of step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline of step 5) of Example 8 Was carried out in a similar manner to Example 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.40-8.34 (m, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.84 (s, 1H), 7.20-7.15 (m, 1H), 7.07 (d, J = 2.9 Hz, 1H), 7.02-6.94 (m, 2H), 6.44 (d, J = 5.2 Hz, 1H), 4.33-4.19 (m, 4H), 4.10 (t, J = 6.5 Hz , 2H), 2.56-2.48 (m, 5H), 1.98-1.85 (m, 3H), 1.71-1.57 (m, 5H), 0.64-0.54 (m, 2H), 0.41-0.31 (m, 2H). MS: 539 [M+H] ⁺ .

Example 54: 1-(2-chloro-4-((5-(3-(piperidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxyno[2] Preparation of ,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 1-(3-chloropropyl)piperidine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same mole of 3-chloro-4-nitrophenol An equivalent was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8. Preparation was carried out in a similar manner to Example 8 except that.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.48-8.41 (m, 1H), 8.22-8.13 (m, 1H), 7.94-7.87 (m, 1H), 7.27-7.21 (m, 1H), 7.17 -7.11 (m, 1H), 7.08-7.01 (m, 2H), 6.54-6.47 (m, 1H), 4.36-4.26 (m, 4H), 4.19-4.10 (m, 2H), 2.58-2.55 (m, 1H), 2.47-2.29 (m, 6H), 1.99-1.91 (m, 2H), 1.55-1.47 (m, 4H), 1.43-1.35 (m, 2H), 0.70-0.61 (m, 2H), 0.46- 0.36 (m, 2H). MS: 553 [M+H] ⁺ .

Example 54

Example 55

Example 55: 1-(2-Chloro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline Preparation of -10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol Was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Then, preparation was carried out in a similar manner as in Example 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.38 (dd, J = 8.8, 5.2 Hz, 1H), 8.14-8.07 (m, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.21- 7.15 (m, 1H), 7.11-7.04 (m, 1H), 7.02-6.94 (m, 2H), 6.45 (dd, J = 8.8, 5.3 Hz, 1H), 4.30-4.18 (m, 4H), 4.15- 4.05 (m, 2H), 3.56-3.49 (m, 4H), 2.53-2.48 (m, 1H), 2.39 (t, J = 7.3 Hz, 2H), 2.36-2.25 (m, 4H), 1.96-1.85 ( m, 2H), 0.63-0.54 (m, 2H), 0.42-0.31 (m, 2H). MS: 555 [M+H] ⁺ .

Example 56: 1-(2-chloro-4-((5-(3-(4-methylpiperazin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxyno Preparation of [2,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 1-(3-chloropropyl)-4-methylpiperazine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and 3-chloro-4-nitrophenol The same molar equivalent of is used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine is used in step 5) of Example 8, 4-chloro-3-(trifluoromethyl)aniline. Preparation was carried out in a similar manner as in Example 8, except that it was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.49-8.39 (m, 1H), 8.17 (dd, J = 9.1, 3.1 Hz, 1H), 7.91 (d, J = 3.0 Hz, 1H), 7.24 ( d, J = 3.5 Hz, 1H), 7.15 (s, 1H), 7.08-7.00 (m, 2H), 6.57-6.47 (m, 1H), 4.39-4.24 (m, 4H), 4.21-4.09 (m, 2H), 2.58-2.55 (m, 1H), 2.50-2.32 (m, 10H), 2.22 (s, 3H), 2.01-1.88 (m, 2H), 0.71-0.61 (m, 2H), 0.49-0.36 ( m, 2H). MS: 568 [M+H] ⁺ .

Example 56

Example 57

Example 57: 1-(4-((5-(3-(4-acetylpiperazin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxyno[2,3 Preparation of -f]quinolin-10-yl)oxy)-2-chlorophenyl)-3-cyclopropylurea

The same molar equivalent of 1-(4-(3-chloropropyl)piperazin-1-yl)ethan-1-one hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and , The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in step 5) of Example 8. Preparation was carried out in a similar manner as in Example 8, except that 3-(trifluoromethyl)aniline was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.90 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.09-7.01 (m, 2H), 6.51 (d, J = 5.1 Hz, 1H), 4.37-4.26 (m, 4H), 4.17 ( t, J = 6.4 Hz, 2H), 3.48-3.39 (m, 4H), 2.58-2.53 (m, 1H), 2.49-2.45 (m, 2H), 2.40 (t, J = 5.0 Hz, 2H), 2.33 (t, J = 5.1 Hz, 2H), 2.02-1.93 (m, 5H), 0.70-0.60 (m, 2H), 0.46-0.36 (m, 2H). MS: 596 [M+H] ⁺ .

Example 58: 1-(2-chloro-4-((5-(3-(1,1-dioxothiomorpholino)propoxy)-2,3-dihydro-[1,4]dioxy Preparation of no[2,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 4-(3-chloropropyl)thiomorpholine-1,1-dioxide hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and 3-chloro-4 -The same molar equivalent of nitrophenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in step 5) of 4-chloro-3- (trifluoro) of Example 8. Preparation was carried out in a similar manner as in Example 8, except that methyl)aniline was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.90 (s, 1H), 7.24 (d, J = 2.6 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.09 (s, 1H), 7.05 (dd, J = 9.1, 2.7 Hz, 1H), 6.51 (d, J = 5.1 Hz, 1H) , 4.36-4.26 (m, 4H), 4.18 (t, J = 6.5 Hz, 2H), 3.14-3.06 (m, 4H), 2.96-2.87 (m, 4H), 2.65 (t, J = 7.0 Hz, 2H ), 2.58-2.55 (m, 1H), 1.99-1.92 (m, 2H), 0.69-0.62 (m, 2H), 0.47-0.37 (m, 2H). MS: 603 [M+H] ⁺ .

Example 58

Example 59

Example 59: 1-(2-chloro-4-((5-(3-(4,4-dimethylpiperidin-1-yl)propoxy)-2,3-dihydro-[1,4] Preparation of dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 1-(3-chloropropyl)-4,4-dimethylpiperidine hydrochloride was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and 3-chloro-4 -The same molar equivalent of nitrophenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in step 5) of 4-chloro-3- (trifluoro) of Example 8. Preparation was carried out in a similar manner as in Example 8, except that methyl)aniline was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.49-8.40 (m, 1H), 8.17 (dd, J = 9.0, 5.8 Hz, 1H), 7.90 (d, J = 5.5 Hz, 1H), 7.27- 7.21 (m, 1H), 7.17-7.11 (m, 1H), 7.05 (dd, J = 6.1, 3.6 Hz, 2H), 6.56-6.47 (m, 1H), 4.37-4.26 (m, 4H), 4.19- 4.11 (m, 2H), 2.59-2.53 (m, 1H), 2.48-2.44 (m, 2H), 2.40-2.31 (m, 4H), 2.00-1.90 (m, 2H), 1.38-1.29 (m, 4H) ), 0.90 (s, 6H), 0.69-0.61 (m, 2H), 0.45-0.37 (m, 2H). MS: 581 [M+H] ⁺ .

Example 60: 1-(2-chloro-4-((5-(3-(4-hydroxy-4-methylpiperidin-1-yl)propoxy)-2,3-dihydro-[1 Preparation of ,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 1-(3-chloropropyl)-4-methylpiperidin-4-ol was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and 3-chloro- The same molar equivalent of 4-nitrophenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in step 5) of Example 8. Preparation was carried out in a similar manner as in Example 8, except that it was used instead of romethyl)aniline.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.56 (d, J = 5.8 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 8.00 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H), 7.26 (s, 2H), 6.64 (d, J = 5.6 Hz, 1H), 4.45-4.32 (m, 4H), 4.26 (t, J = 5.9 Hz, 2H), 3.27-3.24 (m, 2H), 3.18-3.04 (m, 4H), 2.59-2.55 (m, 1H), 2.33-2.26 (m, 2H), 1.90-1.78 (m, 2H), 1.74- 1.62 (m, 2H), 1.27-1.23 (m, 1H), 1.19 (s, 3H), 0.72-0.61 (m, 2H), 0.47-0.37 (m, 2H). MS: 583 [M+H] ⁺ .

Example 61: 1-(4-((5-(3-(4-amino-4-methylpiperidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxy Preparation of no[2,3-f]quinolin-10-yl)oxy)-2-chlorophenyl)-3-cyclopropylurea

1) Step 1-5): tert-butyl (1-(3-((10-(3-chloro-4-(3-cyclopropylureido)phenoxy)-2,3-dihydro-[1, Preparation of 4]dioxyno[2,3-f]quinolin-5-yl)oxy)propyl)-4-methylpiperidin-4-yl)carbamate

The same molar equivalent of tert-butyl (1-(3-chloropropyl)-4-methylpiperidin-4-yl)carbamate was substituted for 1-bromo-2-methoxyethane in step 2) of Example 8 And the same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in step 5) of Example 8. Preparation was carried out in a similar manner to Example 8, except that chloro-3-(trifluoromethyl)aniline was used instead. MS: 682 [M+H] ⁺ .

2) Step 6): The final product (68 mg, 1 mmol) prepared in steps 1-5) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added dropwise thereto. The mixture was reacted for 3 hours. The reaction was quenched with a solution of ammonia in methanol at 0 °C. The reaction solution was evaporated to dryness and purified by column chromatography to obtain 20 mg of a white solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.91 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.15 (d, J = 3.0 Hz, 1H), 7.09-7.00 (m, 2H), 6.50 (d, J = 5.1 Hz, 1H), 4.37-4.26 (m, 4H), 4.14 ( t, J = 6.4 Hz, 2H), 3.39 (s, 2H), 2.58-2.53 (m, 1H), 2.48-2.27 (m, 6H), 1.99-1.86 (m, 2H), 1.50-1.32 (m, 4H), 1.02 (s, 3H), 0.71-0.61 (m, 2H), 0.47-0.37 (m, 2H). MS: 582 [M+H] ⁺ .

Example 62: 1-(2-chloro-4-((5-(3-((2-methoxyethyl)(methyl)amino)propoxy)-2,3-dihydro-[1,4]di Preparation of oxyno[2,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

Step 1-5): 1-(4-((5-(3-bromopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline-10- Preparation of yl)oxy)-2-chlorophenyl)-3-cyclopropylurea

The same molar equivalent of 1,3-dibromoethane was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used in Examples. Except for using instead of p-nitrophenol in step 3) of 8, and using the same molar equivalent of cyclopropylamine instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out in a similar manner to Example 8. MS: 548 [M+H] ⁺ .

2) Step 6): The final product (55 mg, 1 mmol) prepared in steps 1-5) was dissolved in acetonitrile (3 mL), followed by triethylamine (202 mg, 2 mmol) and 2-methoxy-N -Methylethan-1-amine (135 mg, 1.5 mmol) was added. The mixture was reacted at 25° C. for 3 hours. The reaction solution was evaporated to dryness and subjected to column chromatography to obtain 20 mg of a white solid.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.47-8.41 (m, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.90 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 3.0 Hz, 1H), 7.08-7.02 (m, 2H), 6.53-6.48 (m, 1H), 4.37-4.26 (m, 4H), 4.15 (t, J = 6.4 Hz , 2H), 3.41 (t, J = 5.9 Hz, 2H), 3.21 (s, 3H), 2.58-2.55 (m, 1H), 2.54-2.51 (m, 4H), 2.22 (s, 3H), 1.96- 1.87 (m, 2H), 0.70-0.61 (m, 2H), 0.46-0.38 (m, 2H). MS: 557 [M+H] ⁺ .

Example 63: 1-(2-chloro-4-((5-(3-(cyclobutyl(methyl)amino)propoxy)-2,3-dihydro-[1,4]dioxyno[2, Preparation of 3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

Preparation was carried out in a similar manner to Example 62, except that the same molar equivalent of N-methylcyclobutylamine was used instead of 2-methoxy-N-methylethyl-1-amine in step 6) of Example 62.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.91 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.15 (d, J = 3.0 Hz, 1H), 7.05 (d, J = 7.5 Hz, 2H), 6.51 (d, J = 5.1 Hz, 1H), 4.35-4.26 (m, 4H) , 4.15 (t, J = 6.4 Hz, 2H), 2.84-2.74 (m, 1H), 2.59-2.53 (m, 1H), 2.37 (t, J = 7.0 Hz, 2H), 2.05 (s, 3H), 2.02-1.94 (m, 2H), 1.94-1.87 (m, 2H), 1.81-1.70 (m, 2H), 1.63-1.52 (m, 2H), 0.72-0.59 (m, 2H), 0.46-0.37 (m , 2H). MS: 553 [M+H] ⁺ .

Example 63

Example 64

Example 64: 1-(2-chloro-4-((5-((6-(dimethylamino)hexyl)oxy)-2,3-dihydro-[1,4]dioxyno[2,3- f] Preparation of quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 6-chloro-N,N-dimethylhexan-1-amine was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and 3-chloro-4-nitrophenol The same molar equivalent was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8. Preparation was carried out in a similar manner to Example 8 except that it was used.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (dd, J = 5.2, 2.7 Hz, 1H), 8.17 (dd, J = 9.1, 2.7 Hz, 1H), 7.90 (d, J = 2.7 Hz, 1H), 7.28-7.21 (m, 1H), 7.13 (d, J = 2.8 Hz, 1H), 7.07-7.00 (m, 2H), 6.51 (dd, J = 5.2, 2.7 Hz, 1H), 4.38-4.26 (m, 4H), 4.11 (t, J = 6.6 Hz, 2H), 2.58-2.55 (m, 1H), 2.22-2.18 (m, 2H), 2.11 (s, 6H), 1.83-1.75 (m, 2H ), 1.49-1.39 (m, 4H), 1.39-1.28 (m, 2H), 0.76-0.55 (m, 2H), 0.49-0.31 (m, 2H). MS: 555 [M+H] ⁺ .

Example 65: 1-(2-Chloro-4-((5-(oxetan-3-yloxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline Preparation of -10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of oxetan-3-yl 4-methylbenzenesulfonate was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same mole of 3-chloro-4-nitrophenol An equivalent was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8. Preparation was carried out in a similar manner to Example 8 except that.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.18 (d, J = 9.1 Hz, 1H), 7.91 (s, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.05 (dd, J = 9.1, 2.8 Hz, 1H), 6.70 (s, 1H), 6.52 (d, J = 5.2 Hz, 1H) , 5.51-5.41 (m, 1H), 5.02 (t, J = 6.7 Hz, 2H), 4.66-4.58 (m, 2H), 4.39-4.29 (m, 4H), 2.57-2.54 (m, 1H), 0.71 -0.61 (m, 2H), 0.47-0.37 (m, 2H). MS: 484 [M+H] ⁺ .

Example 65

Example 66

Example 66: 1-(2-chloro-4-((5-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro-[1,4]dioxyno[2,3- f] Preparation of quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of tetrahydrofuran-3-yl 4-methylbenzenesulfonate was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same amount of 3-chloro-4-nitrophenol. A molar equivalent was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8. Except that, the preparation was carried out in a similar manner as in Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.45 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 9.1 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.09-7.00 (m, 2H), 6.52 (d, J = 5.2 Hz, 1H), 5.24-5.16 (m, 1H), 4.37- 4.26 (m, 4H), 4.01-3.92 (m, 1H), 3.92-3.83 (m, 2H), 3.83-3.74 (m, 1H), 2.59-2.54 (m, 1H), 2.40-2.26 (m, 1H) ), 2.11-2.00 (m, 1H), 0.70-0.61 (m, 2H), 0.46-0.38 (m, 2H). MS: 498 [M+H] ⁺ .

Example 67: 1-(2-chloro-4-((5-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydro-[1,4]dioxyno[2] Preparation of ,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and 3-chloro-4-nitro The same molar equivalent of phenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in step 5) of Example 8 4-chloro-3-(trifluoromethyl) Preparation was carried out in a similar manner to Example 8, except that it was used instead of aniline.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.37 (d, J = 5.1 Hz, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.83 (s, 1H), 7.18 (d, J = 2.8 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J = 3.0 Hz, 1H), 6.98 (dd, J = 9.1, 2.8 Hz, 1H), 6.44 (d, J = 5.1 Hz, 1H) , 4.78-4.68 (m, 1H), 4.31-4.18 (m, 4H), 3.88-3.76 (m, 2H), 3.52-3.43 (m, 2H), 2.52-2.48 (m, 1H), 2.02-1.97 ( m, 2H), 1.63-1.55 (m, 2H), 0.64-0.54 (m, 2H), 0.40-0.31 (m, 2H). MS: 512 [M+H] ⁺ .

Example 67

Example 68

Example 68: 1-(2-chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-cyclobutylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 1) of Example 1, and the same molar equivalent of cyclobutylamine was used in step 3) of Example 1 to 4-chloro-3. Preparation was carried out in a similar manner as in Example 1, except that -(trifluoromethyl)aniline was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.92 (s, 1H), 7.30-7.19 (m, 2H), 7.11-6.98 (m, 2H), 6.51 (d, J = 5.2 Hz, 1H), 4.37-4.25 (m, 4H), 4.19-4.06 (m, 1H), 3.92 (s, 3H), 2.29 -2.15 (m, 2H), 1.91-1.75 (m, 2H), 1.71-1.54 (m, 2H). MS: 456 [M+H] ⁺ .

Example 69: 1-(2-chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-cyclopentylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 1) of Example 1, and the same molar equivalent of cyclopentylamine was used in step 3) of Example 1 to 4-chloro-3. Preparation was carried out in a similar manner as in Example 8, except that -(trifluoromethyl)aniline was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 9.1 Hz, 1H), 7.92 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.11-6.99 (m, 3H), 6.50 (d, J = 5.2 Hz, 1H), 4.36-4.26 (m, 4H), 4.00-3.87 (m, 4H), 1.91-1.77 (m , 2H), 1.71-1.59 (m, 2H), 1.59-1.48 (m, 2H), 1.45-1.30 (m, 2H). MS: 470 [M+H] ⁺ .

Example 69

Example 70

Example 70: 1-(2-chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-cyclobutylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclobutylamine was used in step 5) of Example 8. Preparation was carried out in a similar manner as in Example 8, except that -(trifluoromethyl)aniline was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 9.1 Hz, 1H), 7.92 (s, 1H), 7.28-7.21 (m, 2H), 7.07 (s, 1H), 7.03 (dd, J = 9.1, 2.8 Hz, 1H), 6.50 (d, J = 5.2 Hz, 1H), 4.35-4.27 (m, 4H), 4.27-4.21 (m , 2H), 4.17-4.08 (m, 1H), 3.77-3.70 (m, 2H), 3.34 (s, 3H), 2.26-2.18 (m, 2H), 1.90-1.78 (m, 2H), 1.71-1.54 (m, 2H). MS: 500 [M+H] ⁺ .

Example 71: 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-cyclopentylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopentylamine was used in step 5) of Example 8. Preparation was carried out in a similar manner as in Example 8, except that -(trifluoromethyl)aniline was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.92 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.11-7.00 (m, 3H), 6.49 (d, J = 5.2 Hz, 1H), 4.38-4.27 (m, 4H), 4.27-4.20 (m, 2H), 4.01-3.88 (m , 1H), 3.77-3.69 (m, 2H), 3.30 (s, 3H), 1.91-1.78 (m, 2H), 1.69-1.60 (m, 2H), 1.60-1.49 (m, 2H), 1.45-1.32 (m, 2H). MS: 514 [M+H] ⁺ .

Example 71

Example 72

Example 72: 1-(2-chloro-4-((5-(3-methoxypropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-cyclobutylurea

The same molar equivalent of 1-bromo-3-methoxypropane was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used. Except that it was used instead of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclobutylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Was carried out in a similar manner to Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.92 (s, 1H), 7.28-7.21 (m, 2H), 7.09-6.99 (m, 2H), 6.53-6.47 (m, 1H), 4.38-4.26 (m, 4H), 4.22-4.07 (m, 3H), 3.51 (t, J = 6.3 Hz, 2H) , 3.27 (s, 3H), 2.26-2.15 (m, 2H), 2.09-1.98 (m, 2H), 1.91-1.76 (m, 2H), 1.70-1.57 (m, 2H). MS: 514 [M+H] ⁺ .

Example 73: 1-(2-chloro-4-((5-(3-methoxypropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-cyclopentylurea

The same molar equivalent of 1-bromo-3-methoxypropane was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used. Except that it was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopentylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Was carried out in a similar manner to Example 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.37 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H), 7.86 (s, 1H), 7.17 (d, J = 2.8 Hz, 1H), 7.02-6.92 (m, 3H), 6.43 (d, J = 5.1 Hz, 1H), 4.30-4.19 (m, 4H), 4.10 (t, J = 6.4 Hz, 2H), 3.93- 3.81 (m, 1H), 3.45 (t, J = 6.3 Hz, 2H), 3.21 (s, 3H), 2.01-1.91 (m, 2H), 1.83-1.73 (m, 2H), 1.64-1.53 (m, 2H), 1.53-1.44 (m, 2H), 1.37-1.25 (m, 2H). MS: 528 [M+H] ⁺ .

Example 73

Example 74

Example 74: 1-(2-chloro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline Preparation of -10-yl)oxy)phenyl)-3-cyclobutylurea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol Was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclobutylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Then, preparation was carried out in a similar manner as in Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.45 (d, J = 5.2 Hz, 1H), 8.18-8.13 (m, 1H), 7.92 (s, 1H), 7.28-7.21 (m, 2H), 7.08 (s, 1H), 7.02 (dd, J = 9.1, 2.8 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H), 4.38-4.26 (m, 4H), 4.25-4.04 (m, 3H) , 3.86-3.51 (m, 4H), 2.69-2.52 (m, 4H), 2.48-2.32 (m, 2H), 2.25-2.15 (m, 2H), 2.15-1.95 (m, 2H), 1.92-1.76 ( m, 2H), 1.71-1.55 (m, 2H). MS: 569 [M+H] ⁺ .

Example 75: 1-(2-chloro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline Preparation of -10-yl)oxy)phenyl)-3-cyclopentylurea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol Was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopentylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Then, preparation was carried out in a similar manner as in Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (d, J = 5.1 Hz, 1H), 8.21 (d, J = 9.1 Hz, 1H), 7.92 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.09-6.98 (m, 3H), 6.49 (d, J = 5.1 Hz, 1H), 4.37-4.26 (m, 4H), 4.16 (t, J = 6.4 Hz, 2H), 4.00- 3.90 (m, 1H), 3.59 (t, J = 4.6 Hz, 4H), 2.46 (t, J = 7.1 Hz, 2H), 2.38 (t, J = 4.6 Hz, 4H), 2.02-1.90 (m, 2H ), 1.90-1.78 (m, 2H), 1.71-1.60 (m, 2H), 1.60-1.49 (m, 2H), 1.45-1.32 (m, 2H). MS: 583 [M+H] ⁺ .

Example 75

Example 76

Example 76: 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinopropoxy)-2,3-dihydro-[ Preparation of 1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and 2-fluoro-5-(trifluoromethyl ) Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of aniline was used instead of 4-chloro-3-(trifluoromethyl)aniline in Step 5) of Example 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.27 (s, 1H), 8.90 (d, J = 2.9 Hz, 1H), 8.62 (dd, J = 7.2, 2.3 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.60-7.46 (m, 3H), 7.45-7.35 (m, 1H), 7.15-7.07 (m, 2H), 7.05 (s, 1H), 6.43 (d, J = 5.2 Hz , 1H), 4.38-4.29 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.6 Hz, 4H), 2.46 (t, J = 7.1 Hz, 2H), 2.42 -2.31 (m, 4H), 2.01-1.91 (m, 2H). MS: 643 [M+H] ⁺ .

Example 77: 1-(4-fluorophenyl)-3-(4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2] Preparation of ,3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of p-fluoroaniline was used in Examples. Preparation was carried out in a similar manner as in Example 8, except that 4-chloro-3-(trifluoromethyl)aniline in step 5) of 8 was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.80 (d, J = 17.3 Hz, 2H), 8.40 (d, J = 5.2 Hz, 1H), 7.57-7.51 (m, 2H), 7.50-7.44 ( m, 2H), 7.16-7.02 (m, 5H), 6.41 (d, J = 5.2 Hz, 1H), 4.39-4.28 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.59 (t , J = 4.6 Hz, 4H), 2.49-2.45 (m, 2H), 2.40 (t, J = 4.6 Hz, 4H), 2.01-1.91 (m, 2H). MS: 575 [M+H] ⁺ .

Example 77

Example 78

Example 78: 1-(2,4-fluorophenyl)-3-(4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno Preparation of [2,3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 2,4-difluoroaniline Preparation was carried out in a similar manner to Example 8, except that the 4-chloro-3-(trifluoromethyl)aniline of Example 8 was used instead of the aniline.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.15 (d, J = 3.4 Hz, 1H), 8.55 (d, J = 3.0 Hz, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.12 -8.02 (m, 1H), 7.57-7.49 (m, 2H), 7.36-7.26 (m, 1H), 7.12-7.06 (m, 2H), 7.06-7.00 (m, 2H), 6.41 (d, J = 5.2 Hz, 1H), 4.37-4.29 (m, 4H), 4.16 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.6 Hz, 4H), 2.46 (t, J = 7.2 Hz, 2H) , 2.43-2.31 (m, 4H), 2.01-1.92 (m, 2H). MS: 593 [M+H] ⁺ .

Example 79: 1-(2-chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-methylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 1) of Example 1, and the same molar equivalent of methylamine was used in step 3) of Example 1 to 4-chloro-3- Preparation was carried out in a similar manner to Example 1, except that (trifluoromethyl)aniline was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.45 (d, J = 5.1 Hz, 1H), 8.14 (d, J = 9.0 Hz, 1H), 8.05 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.09-7.01 (m, 2H), 6.89-6.78 (m, 1H), 6.52 (d, J = 5.1 Hz, 1H), 4.37-4.27 (m, 4H), 3.92 (s, 3H ), 2.66 (d, J = 4.5 Hz, 3H). MS: 416 [M+H] ⁺ .

Example 79

Example 80

Example 80: 1-(2-chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-ethylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 1) of Example 1, and the same molar equivalent of ethylamine was used in step 3) of Example 1 to 4-chloro-3- Preparation was carried out in a similar manner to Example 1, except that (trifluoromethyl)aniline was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.07 (s, 1H), 7.04 (dd, J = 9.1, 2.8 Hz, 1H), 6.95-6.90 (m, 1H), 6.51 (d, J = 5.2 Hz, 1H), 4.36- 4.27 (m, 4H), 3.92 (s, 3H), 3.17-3.07 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H). MS: 430 [M+H] ⁺ .

Example 81: 1-(2-chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-propylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 1) of Example 1, and the same molar equivalent of propylamine was used in step 3) of Example 1 to 4-chloro-3- Preparation was carried out in a similar manner to Example 1, except that (trifluoromethyl)aniline was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 9.1 Hz, 1H), 8.01 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.07 (s, 1H), 7.04 (dd, J = 9.1, 2.8 Hz, 1H), 6.97 (d, J = 5.6 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H) , 4.41-4.23 (m, 4H), 3.92 (s, 3H), 3.11-3.02 (m, 2H), 1.50-1.38 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). MS: 444 [M+H] ⁺ .

Example 81

Example 82

Example 82: 1-(2-chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-isopropylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 1) of Example 1, and the same molar equivalent of isopropylamine was used in step 3) of Example 1 to 4-chloro-3. Preparation was carried out in a similar manner as in Example 1, except that -(trifluoromethyl)aniline was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 9.1 Hz, 1H), 7.93 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.07 (s, 1H), 7.04 (dd, J = 9.0, 2.8 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.50 (d, J = 5.2 Hz, 1H) , 4.35-4.24 (m, 4H), 3.92 (s, 3H), 3.80-3.70 (m, 1H), 1.11 (d, J = 6.5 Hz, 6H). MS: 444 [M+H] ⁺ .

Example 83: 1-(2-chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy) Preparation of phenyl)-3-isobutylurea

The same molar equivalent of 3-chloro-4-nitrophenol was used in place of p-nitrophenol in step 1) of Example 1, and the same molar equivalent of isobutylamine was used in step 3) of Example 1 to 4-chloro-3. Preparation was carried out in a similar manner as in Example 1, except that -(trifluoromethyl)aniline was used instead.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.05 (s, 1H), 7.24 (d, J = 2.7 Hz, 1H), 7.07 (s, 1H), 7.04 (dd, J = 9.1, 2.8 Hz, 1H), 7.02-6.98 (m, 1H), 6.51 (d, J = 5.1 Hz, 1H), 4.38- 4.23 (m, 4H), 3.92 (s, 3H), 3.00-2.87 (m, 2H), 1.73-1.64 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H). MS: 458 [M+H] ⁺ .

Example 83

Example 84

Example 84: 1-cyclopropyl-3-(2-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-day)oxy)phenyl)urea

The same molar equivalent of 3-fluoro-4-nitrophenol was used in place of p-nitrophenol in step 1) of Example 1, and the same molar equivalent of cyclopropylamine was used in step 1) of Example 1, 4-chloro- Preparation was carried out in a similar manner as in Example 1, except that 3-(trifluoromethyl)aniline was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.17-8.05 (m, 2H), 7.15-7.03 (m, 2H), 6.87 (dd, J = 8.7 , 2.5 Hz, 1H), 6.76 (d, J = 2.9 Hz, 1H), 6.50 (d, J = 5.2 Hz, 1H), 4.38-4.26 (m, 4H), 3.92 (s, 3H), 2.59-2.52 (m, 1H), 0.70-0.59 (m, 2H), 0.45-0.34 (m, 2H). MS: 426 [M+H] ⁺ .

Example 85: 1-(2-Chloro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline Preparation of -10-yl)oxy)phenyl)-3-methylurea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol Was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of methylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Was carried out in a similar manner to Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H), 8.03 (s, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.07-7.00 (m, 2H), 6.81 (d, J = 4.7 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H), 4.36-4.26 (m, 4H), 4.16 ( t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.6 Hz, 4H), 2.66 (d, J = 4.5 Hz, 3H), 2.46 (t, J = 7.1 Hz, 2H), 2.42-2.33 ( m, 4H), 2.01-1.90 (m, 2H). MS: 529 [M+H] ⁺ .

Example 85

Example 86

Example 86: 1-(2-chloro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline Preparation of -10-yl)oxy)phenyl)-3-ethylurea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol Was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of ethylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8. Was carried out in a similar manner to Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.1 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.98 (s, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.08-7.00 (m, 2H), 6.97-6.90 (m, 1H), 6.50 (d, J = 5.1 Hz, 1H), 4.36-4.27 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.6 Hz, 4H), 3.18-3.06 (m, 2H), 2.46 (t, J = 7.1 Hz, 2H), 2.42-2.33 (m, 4H), 2.02 -1.91 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H). MS: 543 [M+H] ⁺ .

Example 87: 1-(2-Chloro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline Preparation of -10-yl)oxy)phenyl)-3-propylurea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol Was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of propylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Was carried out in a similar manner to Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 8.00 (s, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.08-7.00 (m, 2H), 7.00-6.93 (m, 1H), 6.50 (d, J = 5.1 Hz, 1H), 4.36-4.27 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.6 Hz, 4H), 3.10-3.02 (m, 2H), 2.46 (t, J = 7.1 Hz, 2H), 2.42-2.34 (m, 4H), 2.01 -1.89 (m, 2H), 1.52-1.38 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). MS: 557 [M+H] ⁺ .

Example 87

Example 88

Example 88: 1-(2-chloro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline Preparation of -10-yl)oxy)phenyl)-3-isopropylurea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol Was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of isopropylamine was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Then, preparation was carried out in a similar manner as in Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 9.1 Hz, 1H), 7.92 (s, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.07-7.00 (m, 2H), 6.90 (d, J = 7.3 Hz, 1H), 6.49 (d, J = 5.2 Hz, 1H), 4.36-4.27 (m, 4H), 4.16 ( t, J = 6.4 Hz, 2H), 3.83-3.69 (m, 1H), 3.59 (t, J = 4.6 Hz, 4H), 2.46 (t, J = 7.1 Hz, 2H), 2.42-2.34 (m, 4H ), 2.02-1.90 (m, 2H), 1.11 (d, J = 6.5 Hz, 6H). MS: 557 [M+H] ⁺ .

Example 89: 1-(2-chloro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline Preparation of -10-yl)oxy)phenyl)-3-isobutylurea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol Was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of isobutylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Then, preparation was carried out in a similar manner as in Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.46 (d, J = 5.2 Hz, 1H), 8.19 (d, J = 9.1 Hz, 1H), 8.06 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.11 (s, 1H), 7.07-6.97 (m, 2H), 6.53 (d, J = 5.2 Hz, 1H), 4.38-4.28 (m, 4H), 4.23 (t, J = 6.0 Hz, 2H), 3.90-3.72 (m, 4H), 3.53-3.46 (m, 2H), 3.13-3.07 (m, 4H), 2.94 (t, J = 6.2 Hz, 2H), 2.24-2.13 (m, 2H), 1.76-1.63 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H). MS: 571 [M+H] ⁺ .

Example 89

Example 90

Example 90: 1-cyclopropyl-3-(4-((5-ethoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy )-2-fluorophenyl)urea preparation

The same molar equivalent of bromoethane was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-fluoro-4-nitrophenol was used in step 3 of Example 8. ) In place of p-nitrophenol, and the same molar equivalent of cyclopropylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8. Preparation was carried out by the method.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (d, J = 5.2 Hz, 1H), 8.18-8.03 (m, 2H), 7.17-6.98 (m, 2H), 6.87 (dd, J = 9.0 , 2.8 Hz, 1H), 6.77 (d, J = 2.9 Hz, 1H), 6.49 (d, J = 5.2 Hz, 1H), 4.38-4.23 (m, 4H), 4.18 (q, J = 7.0 Hz, 2H ), 2.58-2.52 (m, 1H), 1.41 (t, J = 7.0 Hz, 3H), 0.68-0.58 (m, 2H), 0.48-0.33 (m, 2H). MS: 440 [M+H] ⁺ .

Example 91: 1-cyclopropyl-3-(2-fluoro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxyno[2, Preparation of 3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 3-fluoro-4-nitrophenol was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in step 5) of Example 8 to 4-chloro- Preparation was carried out in a similar manner as in Example 8, except that 3-(trifluoromethyl)aniline was used instead.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (d, J = 5.1 Hz, 1H), 8.17-8.06 (m, 2H), 7.16-7.04 (m, 2H), 6.88 (dd, J = 9.0 , 2.8 Hz, 1H), 6.76 (d, J = 2.9 Hz, 1H), 6.50 (d, J = 5.2 Hz, 1H), 4.38-4.27 (m, 4H), 4.27-4.19 (m, 2H), 3.78 -3.70 (m, 2H), 3.34 (s, 3H), 2.58-2.53 (m, 1H), 0.76-0.55 (m, 2H), 0.49-0.34 (m, 2H). MS: 470 [M+H] ⁺ .

Example 91

Example 92

Example 92: 1-cyclopropyl-3-(2-fluoro-4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1,4]dioxyno[2) Preparation of ,3-f]quinolin-10-yl)oxy)phenyl)-3-urea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same mole of 3-fluoro-4-nitrophenol An equivalent was used in place of p-nitrophenol in step 3) of Example 8, and the same molar equivalent of cyclopropylamine was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8. Preparation was carried out in a similar manner to Example 8 except that.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (d, J = 5.2 Hz, 1H), 8.16-8.06 (m, 2H), 7.13-7.03 (m, 2H), 6.87 (dd, J = 9.0 , 2.7 Hz, 1H), 6.76 (d, J = 2.9 Hz, 1H), 6.50 (d, J = 5.2 Hz, 1H), 4.35-4.26 (m, 4H), 4.16 (t, J = 6.4 Hz, 2H ), 3.59 (t, J = 4.6 Hz, 4H), 2.59-2.53 (m, 1H), 2.46 (t, J = 7.1 Hz, 2H), 2.42-2.33 (m, 4H), 2.02-1.92 (m, 2H), 0.68-0.59 (m, 2H), 0.43-0.36 (m, 2H). MS: 539 [M+H] ⁺ .

Example 93: 1-(2-Chloro-4-((5-(3-cyanopropoxy)-2,3-dihydro-[1,4]dioxyno[2,3-f]quinoline- Preparation of 10-yl)oxy)phenyl)-3-cyclopropylurea

The same molar equivalent of 4-bromobutyronitrile was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and the same molar equivalent of 3-chloro-4-nitrophenol was used in Examples. Except for using instead of p-nitrophenol in step 3) of 8, and using the same molar equivalent of cyclopropylamine instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 Preparation was carried out in a similar manner to Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.45 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.90 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.18-6.99 (m, 3H), 6.53 (d, J = 5.2 Hz, 1H), 4.39-4.25 (m, 4H), 4.20 (t, J = 6.2 Hz, 2H), 2.69 ( t, J = 7.2 Hz, 2H), 2.61-2.55 (m, 1H), 2.18-2.06 (m, 2H), 0.70-0.59 (m, 2H), 0.48-0.36 (m, 2H). MS: 495 [M+H] ⁺ .

Example 93

Example 94

Example 94: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-cyanopropoxy)-2,3-dihydro-[1, 4] Preparation of dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 4-bromobutyronitrile was used instead of 1-bromo-2-methoxyethane in step 2) of Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.19 (s, 1H), 8.95 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H) , 7.69-7.58 (m, 2H), 7.58-7.50 (m, 2H), 7.13-7.05 (m, 3H), 6.44 (d, J = 5.2 Hz, 1H), 4.39-4.29 (m, 4H), 4.20 (t, J = 6.2 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.18-2.06 (m, 2H). MS: 599 [M+H] ⁺ .

Example 95: 1-(4-((5-methoxy-2,3-dihydro-[1,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)-3 Preparation of -(2-methyl-5-(trifluoromethyl)phenyl)urea

Similar to Example 1, except that the same molar equivalent of 2-methyl-5-(trifluoromethyl)aniline was used in place of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 1 Preparation was carried out by the method.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.32 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.20 (s, 1H) , 7.62-7.53 (m, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.31-7.23 (m, 1H), 7.13-7.03 (m, 3H), 6.44 (d, J = 5.3 Hz, 1H ), 4.38-4.28 (m, 4H), 3.92 (s, 3H), 2.34 (s, 3H). MS: 526 [M+H] ⁺ .

Example 95

Example 96

Example 96: 1-(2-methyl-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinopropoxy)-2,3-dihydro-[1 Preparation of ,4]dioxyno[2,3-f]quinolin-10-yl)oxy)phenyl)urea

The same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was used in place of 1-bromo-2-methoxyethane in step 2) of Example 8, and 2-methyl-5-(trifluoromethyl) Preparation was carried out in a similar manner as in Example 8, except that the same molar equivalent of aniline was used instead of 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.30 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.19 (s, 1H) , 7.60-7.53 (m, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.27 (dd, J = 7.9, 1.8 Hz, 1H), 7.12-7.06 (m, 2H), 7.05 (s, 1H) ), 6.43 (d, J = 5.2 Hz, 1H), 4.38-4.29 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.5 Hz, 4H), 2.46 (t , J = 7.1 Hz, 2H), 2.39 (s, 4H), 2.34 (s, 3H), 2.01-1.92 (m, 2H). MS: 639 [M+H] ⁺ .

Biological Example 1. Analysis of small molecule compounds to inhibit the activity of RET kinase

The analysis is based on the LANCE TR-FRET technology of Perkin Elmer Inc., and the analysis method is as follows:

1. Dilution of compound: A total of 11 concentrations were obtained using a 3-fold gradient dilution at the highest concentration of 2500 nM (the maximum final concentration of the drug used in this assay was 2500 nM and the minimum final concentration was Was 0.042 nM).

2. 2.5 μL of gradient-diluted compound was taken into a 384-well plate with a transfer pipette.

3. Enzyme addition: 5 μL of 2X RET kinase solution (concentration is 0.8 nM) was taken into the corresponding reaction wells of a 384-well plate with a transfer pipette, mixed well, and pre-reacted for 30 minutes at room temperature.

4. A 2.5 μL 4X Ultra ULight ^™ -JAK-1 (Tyr1023) peptide (concentration is 200 nM)/ATP (concentration is 40 μM) mixture was taken into the corresponding reaction wells of a 384-well plate by a transfer pipette.

5. Negative control: 2.5 μL/well 4X substrate/ATP mixture and 7.5 μL 1X Kinase Assay Buffer were added to the wells of a 384-well plate.

Positive control: 2.5 μL/well 4X substrate/ATP mixture, 2.5 μL/well 1X kinase assay buffer and 5 μL/well 2X RET kinase solution containing 16% DMSO were added to 384-well plates. The final concentration of DMSO in the reaction system was 4%.

6. The mixture was mixed well, then centrifuged and reacted at room temperature in the dark for 60 minutes.

7. Termination of enzymatic reaction: 5 μL of 4X stop solution was taken into the well of a 384-well plate with a transfer pipette, mixed, centrifuged, and reacted at room temperature for 5 minutes.

8. Development of reaction: During color development, 5 μL of 4X detection solution was taken into the wells of a 384-well plate with a transfer pipette, the mixture was mixed and then centrifuged and reacted for 60 minutes at room temperature.

9. The 384-well plate was placed in an Envision plate reader and signals were detected using an appropriate program.

10. Analysis and processing of raw data:

The drug concentration and the corresponding inhibition rate were entered into GraphPad Prism5 for calculation and the inhibition rate of the compound was calculated as follows: Inhibition rate (%) = (recording of positive wells-recording of experimental wells) / (recording of positive control wells-negative control Recording of wells) x 100%. Treatment with GraphPad Prism5 software yielded the corresponding IC ₅₀ value (the concentration of the compound at which 50% of the highest inhibition of the enzyme was achieved).

Table 1 lists the assay results of the inhibitory activity of some of the compounds disclosed herein against RET tyrosine kinase, where A indicates that the IC ₅₀ is less than or equal to 50 nM, and B indicates the IC ₅₀ is greater than 50 nM and less than or equal to 500 nM. And C indicates that the IC ₅₀ is greater than 500 nM and less than 5000 nM and D indicates that the IC ₅₀ is greater than 5000 nM.

Table 1. Analysis results of the inhibitory activity of the compounds disclosed herein against RET tyrosine kinase

Example number RET IC ₅₀ (nM) Example number RET IC ₅₀ (nM) One A 49 A 2 A 50 A 3 B 51 A 4 B 52 A 5 A 53 A 6 A 54 A 7 A 55 A 8 A 56 A 9 B 57 A 10 B 58 A 11 C 59 A 12 B 60 A 13 B 61 A 14 A 62 A 15 B 63 A 16 B 64 A 17 A 65 A 18 A 66 A 19 A 67 A 20 B 68 A 21 A 69 A 22 A 70 A 23 B 71 A 24 A 72 A 25 A 73 B 26 A 74 A 27 A 75 A 28 A 76 A 29 A 77 A 30 A 78 A 31 B 79 A 32 B 80 A 33 B 81 A 34 A 82 A 35 A 83 B 36 A 84 A 37 A 85 A 38 B 86 A 39 B 87 A 40 A 88 A 41 B 89 A 42 A 90 A 43 A 91 A 44 A 92 A 45 A 93 A 46 A 94 A 47 A 95 A 48 A 96 A

Biological Example 2. Analysis of small molecule compounds for inhibiting the activity of VEGFR-2 kinase

The analysis is based on Perkin Elmer Inc.'s LANCE TR-FRET technology and the analysis method is as follows:

1. Dilution of compound: A total of 11 concentrations were obtained using a 3-fold gradient dilution at the highest concentration of 2500 nM (the maximum final concentration of the drug used in this assay was 2500 nM and the minimum final concentration was 0.042 nM). .

2. 2.5 μL of gradient-diluted compound was taken into a 384-well plate with a transfer pipette.

3. Enzyme addition: 5 μL of 2X VEGFR-2 kinase solution (concentration is 0.5 nM) was taken into the corresponding reaction well of a 384-well plate with a transfer pipette, mixed well, and pre-reacted for 30 minutes at room temperature.

4. A 2.5 μL 4X Ultra ULight ^™ -JAK-1 (Tyr1023) peptide (concentration is 200 nM)/ATP (concentration is 40 μM) mixture was taken into the corresponding reaction wells of a 384-well plate by a transfer pipette.

5. Negative control: 2.5 μL/well 4X substrate/ATP mixture and 7.5 μL 1X Kinase Assay Buffer were added to the wells of a 384-well plate.

6. Positive control: 2.5 μL/well 4X substrate/ATP mixture, 2.5 μL/well 1X kinase assay buffer containing 16% DMSO and 5 μL/well 2X VEGFR-2 kinase solution were added to a 384-well plate. The final concentration of DMSO in the reaction system was 4%.

7. The mixture was mixed well, then centrifuged and reacted at room temperature in the dark for 60 minutes.

8. Termination of enzymatic reaction: 5 μL of 4X stop solution was taken into the wells of a 384-well plate with a transfer pipette, mixed, centrifuged, and reacted at room temperature for 5 minutes.

9. Development of reaction: During color development, 5 μL of 4X detection solution was taken into the wells of a 384-well plate with a transfer pipette, the mixture was mixed and then centrifuged and reacted at room temperature for 60 minutes.

10. A 384-well plate was placed in an Envision plate reader and signals were detected using an appropriate program.

11. Analysis and processing of raw data:

The drug concentration and the corresponding inhibition rate were entered into GraphPad Prism5 for calculation and the inhibition rate of the compound was calculated as follows: Inhibition rate (%) = (recording of positive wells-recording of experimental wells) / (recording of positive control wells-negative control Of wells) x 100%. Treatment with GraphPad Prism5 software yielded the corresponding IC ₅₀ value (the concentration of the compound at which 50% of the highest inhibition of the enzyme was achieved).

Table 2 lists the assay results of the inhibitory activity of some of the compounds disclosed herein against VEGFR2 tyrosine kinase, where A indicates that IC ₅₀ is 50 nM or less, and B indicates IC ₅₀ is greater than 50 nM and 500 nM or less. And C indicates that the IC ₅₀ is greater than 500 nM and less than 5000 nM and D indicates that the IC ₅₀ is greater than 5000 nM.

Table 2. Analysis results of the inhibitory activity of some of the compounds disclosed herein against VEGFR2 tyrosine kinase

Example number VEGFR-2 IC ₅₀ (nM) Example number VEGFR-2 IC ₅₀ (nM) One A 58 A 5 B 59 A 6 B 60 A 7 A 61 A 8 B 62 A 9 B 63 A 14 A 64 A 17 A 66 A 18 A 70 A 19 A 72 A 21 A 74 A 25 A 77 A 26 A 78 A 27 B 79 A 28 A 80 A 30 B 81 A 36 B 84 A 43 A 85 A 46 A 86 A 47 A 87 A 48 A 88 A 49 A 89 A 50 A 90 A 51 A 91 A 52 A 92 A 53 A 93 A 54 A 94 B 55 A 95 A 56 A 96 B 57 A

The biological data provided by this disclosure indicate that the compounds disclosed herein are useful for the treatment or prevention of diseases due to abnormalities of VEGFR-2 and RET kinase. Accordingly, the compounds disclosed herein are useful for the treatment of cancers, including primary and metastatic cancers, including solid tumors. Such cancers include, but are not limited to: non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colon Colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia ( chronic granulocytic leukemia), acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma (B- cell and T-cell lymphoma), lymphoma, multiple myeloma, biliary cancer and sarcoma, and cholangiocarcinoma. The compounds disclosed herein also treat cancers that are resistant to one or more other treatment methods. The compounds disclosed herein can also be used for other diseases (other than cancer) associated with VEGFR-2 kinase and/or RET kinase, including but not limited to: ocular fundus disease, psoriasis ), rheumatic arthritis, atherosclerosis, pulmonary fibrosis, liver fibrosis. The compounds disclosed herein may be used as single therapy or combination therapy, and may be used in combination with a plurality of compounds disclosed herein or in combination with drugs other than the present disclosure.

The above-described aspects are only preferred aspects of the present disclosure and are not intended to limit the present disclosure. All modifications, equivalent substitutions and improvements made within the spirit and principle of the present disclosure should be included within the protection scope of the present disclosure.

Claims (16)

A compound of formula (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof:

Formula (I)
(In the formula (I),
X is O or NH;
Y is CH;
Z is CH;
R ¹ is H; C ₁ -C ₉ alkyl; C ₃ -C ₇ cycloalkyl; 4 to 7 membered heterocyclyl; C ₁ -C ₆ alkyl substituted with C ₃ -C ₇ cycloalkyl; Or C ₁ -C ₆ alkyl substituted with 4 to 7 membered heterocyclyl; Or hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, unsubstituted amino, and mono- or di -C ₁ -C cost of one or more of the substituted amino-substituted C ₁ -C ₆ alkyl _{9 is} alkyl,
At this time, the 4 to 7 membered heterocyclyl is a 4 to 7 membered heterocyclyl containing 1 to 2 atoms selected from the group consisting of N, O, and S, and the heterocyclyl is unsubstituted or C ₁ Substituted with -C ₆ alkyl or C ₁ -C ₃ acyl, or oxidized with 1 to 2 oxygen atoms;
R ² is H or halogen;
R ³ is H or halogen;
R ⁴ is H or halogen;
R ⁵ is H; C ₁ -C ₉ alkyl; C ₃ -C ₈ cycloalkyl; C ₁ -C ₆ alkyl substituted with C ₃ -C ₈ cycloalkyl; Or unsubstituted aryl or heteroaryl; Or amino substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkyl, unsubstituted amino, halogen, trifluoromethyl , An aryl or heteroaryl group substituted with at least one of aryloxy and methylsulfonyl,
At this time, the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms, and contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S in the ring).
The method of claim 1,
R ¹ is H; C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; 5 to 6 membered heterocyclyl; C ₁ -C ₃ alkyl substituted with C ₃ -C ₆ cycloalkyl; Or C ₁ -C ₃ alkyl substituted with 5 to 6 membered heterocyclyl; Or hydroxyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, unsubstituted amino, and mono- or di -C ₁ -C cost of one or more of the substituted _{amino-3-alkyl} substituted C ₁ -C ₆ alkyl,
At this time, the 5 to 6 membered heterocyclyl is a 5 to 6 membered heterocyclyl containing 1 to 2 atoms selected from the group consisting of N, O, and S, wherein the heterocyclyl is unsubstituted or C _1- A compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, which is substituted with C ₃ alkyl or C ₁ -C ₃ acyl or is oxidized with 1 to 2 oxygen atoms.
The method of claim 2,
R ¹ is a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, selected from the group consisting of:
H, methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl ( tetrahydro-2H-pyran-4-yl), tetrahydropyrrol-1-ylethyl, tetrahydropyrrol-1-ylpropyl, piperidin-1-ylethyl ), piperidin-1-ylpropyl, piperazin-1-ylethyl, piperazin-1-ylpropyl, morpholin-4-ylethyl, morpholine Folin-4-ylpropyl, methylpiperazin-4-ylethyl, methylpiperazin-4-ylpropyl, N-formylpiperazin-4-ylethyl (N-formylpiperazin-4- ylethyl), N-formylpiperazin-4-ylpropyl, N-acetylpiperazin-4-ylethyl, N-acetylpiperazin-4-ylpropyl, (1,1 -Dioxothiomorpholine)-4-ylethyl ((1,1-dioxothiomorpholin)-4-ylethyl), (1,1-dioxothiomorpholin)-4-ylpropyl, methylthioethyl, methylthiopropyl , Dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminoethyl, diethylaminopropyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl, aminopropyl, amino Butyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, (3S)-3-aminobutyl, (3R)-3-aminobutyl, (3S)-3-hydroxybutyl and (3R)-3-hydroxybutyl.
The method of claim 1,
R ¹ is a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, selected from the group consisting of:
Butyl, isobutyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, 4,4-dimethylpiperidin-1-ylethyl, 4,4-dimethylpiperidin-1-ylpropyl, dimethylaminopentyl, dimethylaminohexyl, and oxetan-3-yl.
The method of claim 1,
The halogen in R ² , R ³ , and R ⁴ is F, Cl or Br, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof.
The method of claim 1,
R ⁵ is H; C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; C ₁ -C ₃ alkyl substituted with C ₃ -C ₆ cycloalkyl; Or unsubstituted aryl or heteroaryl; Or amino substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkyl, unsubstituted amino, halogen, trifluoromethyl , Aryloxy or methylsulfonyl substituted aryl or heteroaryl at least one,
At this time, the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms, which contains 1 to 2 atoms selected from the group consisting of N, O, and S in the ring, Or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof.
The method of claim 1,
R ⁵ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl substituted with C ₃ -C ₆ cycloalkyl, or unsubstituted phenyl, naphthyl or heteroaryl; Or methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino , Phenyl, naphthyl, or heteroaryl group substituted with one or more of fluorine, chlorine, bromine, trifluoromethyl, phenoxy or methylsulfonyl,
At this time, the heteroaryl group is pyridinyl, pyrimidinyl, quinolinyl, quinazolinyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, And a compound selected from the group consisting of pyrrolyl, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof.
The method of claim 1,
R ⁵ is a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, selected from the group consisting of:
H, methyl, ethyl, propyl, isopropyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluoro Phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-phenoxyphenyl, 3-(methylsulfonyl)phenyl, 4-(methylsulfonyl)phenyl, 2,4-difluorophenyl, 2,5 -Difluorophenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-(trifluoromethyl)phenyl , 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 3-(tri Fluoromethyl)-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-chlorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-5-chlorophenyl , 3-chloro-4-fluorophenyl, 2-chloro-4-(trifluoromethyl)phenyl, 2-chloro-5-(trifluoromethyl)phenyl, 3-chloro-4-(trifluoromethyl )Phenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl , 3-chloro-4-fluorophenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methoxy-pyridin-4-yl, 3-methyl-isoxazol-5-yl , And naphthalen-1-yl.
The method of claim 1,
R ⁵ is a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, selected from the group consisting of:
Butyl, isobutyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-5-(trifluoromethyl)phenyl, 2-methyl-4-(trifluoromethyl)phenyl, 3-methyl-4 -(Trifluoromethyl)phenyl, 3-methyl-5-(trifluoromethyl)phenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, and 3-chloro-4-methylphenyl.
A compound of formula (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof:

Formula (I)
(In the formula (I),
X is O or NH;
Y is CH;
Z is CH;
R ¹ is 1 to 3 selected from the group consisting of C ₁ -C ₃ acyl, halogen, trifluoromethyl, cyano, -CONH ₂ , -NR ^a R ^b and a 4 to 7 membered heteroalicyclic group. C ₁ -C ₆ alkyl substituted with a substituent, wherein the 4 to 7 membered heteroalicyclic group is a 4 to 7 membered heteroali containing 1 to 2 atoms selected from the group consisting of N, O, and S as ring atoms It is a cyclic group, and the 4 to 7 membered heteroalicyclic group is substituted with 1 to 3 substituents selected from the group consisting of halogen, C ₁ -C ₃ alkyl, hydroxyl, -NH ₂ , and C ₁ -C ₃ acyl Become,
R ^a and R ^b are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C a C ₁ -C ₆ alkyl, C ₁ -C ₃ alkylthio substituted with ₃ alkoxy and substituted C ₁ -C ₆ alkyl, or substituted amino or unsubstituted C ₁ -C ₆ alkyl substituted by unsubstituted amino, wherein the substituted amino is mono- or di-substituted with -C ₁ -C ₃ alkyl;
R ² , R ³ , and R ⁴ are each independently H or halogen;
R ⁵ is H; C ₁ -C ₉ alkyl; C ₃ -C ₈ cycloalkyl; C ₁ -C ₆ alkyl substituted with C ₃ -C ₈ cycloalkyl; Is unsubstituted aryl or heteroaryl; Or an aryl or heteroaryl group substituted with 1 to 3 substituents -B, wherein the substituents -B are each independently hydroxyl, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C _1- Amino, unsubstituted amino, halogen, trifluoromethyl, aryloxy or methylsulfonyl substituted with C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkyl,
At this time, the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms, and contains 1 to 3 atoms selected from the group consisting of N, O, and S in the ring).
The method of claim 10,
R ¹ is -F, trifluoromethyl, cyano, -CONH ₂ , -NR ^a R ^b , and C ₁ -C substituted with 1 to 3 substituents selected from the group consisting of 4 to 7 membered heteroalicyclic groups ₆ alkyl, wherein the 4 to 7 membered heteroalicyclic group is a 4 to 7 membered heteroalicyclic group containing 1 to 2 atoms selected from the group consisting of N, O, and S as ring atoms, the 4 to The 7 membered heteroalicyclic group is substituted with 1 to 3 substituents selected from the group consisting of -F, C ₁ -C ₃ alkyl, hydroxyl, -NH ₂ , and C ₁ -C ₃ acyl,
R ^a and R ^b are each independently H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl substituted with C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio. and substituted C ₁ -C ₃ alkyl, or substituted or unsubstituted amino-substituted amino substituted with C ₁ -C ₃ alkyl, wherein the substituted amino is a single or double substituted with C ₁ -C ₃ alkyl;
R ⁵ is H; C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; C ₁ -C ₃ alkyl substituted with C ₃ -C ₆ cycloalkyl; Is unsubstituted phenyl, naphthyl or heteroaryl; Or a phenyl, naphthyl or heteroaryl group substituted with 1 to 3 substituents -B, wherein the substituents -B are each independently methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopro Foxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, fluorine, chlorine, bromine, trifluoromethyl, phenoxy or methylsulfonyl,
At this time, the heteroaryl group is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, quinazolinyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, and pyrrolyl Phosphorus, a compound, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof.
The method according to any one of claims 1 to 11,
The pharmaceutically acceptable salt of the compound is one selected from the group consisting of one or more of the following salts, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof: hydrochloride, hydrobromide , Hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoic acid Salt, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, salicylate, Hexonate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, Sodium salt and zinc salt.
A method for preparing the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof,
The manufacturing method is
Reaction of the compound of formula (II) with H ₂ NR ⁵ to prepare a compound of formula (I):

(In the formula X, Y, Z, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined in any one of claims 1 to 9 or 10 to 11)
Containing, the manufacturing method.
A pharmaceutical composition for treating diseases associated with tyrosine kinase VEGFR-2, C-RAF, B-RAF, or RET, wherein the composition is a compound of formula (I) according to any one of claims 1 to 11 , Or a pharmaceutically acceptable salt, hydrate, or prodrug thereof; And a pharmaceutically acceptable carrier(s) or excipient(s).
As a pharmaceutical composition, the composition comprises, as an active ingredient, the compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; One or more other therapeutic agents; And one or more pharmaceutically acceptable carriers or excipients.
A compound of formula (I) according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of tyrosine kinase VEGFR-2, C-RAF, B-RAF, or RET-related diseases, or As the use of a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof,
These diseases include ocular fundus disease, psoriasis, rheumatic arthritis, atherosclerosis, pulmonary fibrosis, liver fibrosis, and non-small cell lung cancer. -small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, stomach cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia ), acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma (B-cell and T -cell lymphoma), lymphoma, multiple myeloma (multiple myeloma), biliary cancer (biliary cancer) and sarcoma, and cholangiocarcinoma (cholangiocarcinoma).